Experiment 4

Williamson Ether Synthesis

Background

Many of the reactions used in organic chemistry are described as being named reactions.  The Fischer esterification was a named reaction, referring to Emil Fischer who discovered and popularized it as a method to produce esters.  The Williamson ether synthesis is another named reaction, which also describes a specific type of reaction.  In this reaction, an alcohol is converted into a nucleophile (using base) and reacts via a S_N2 reaction mechanism with an alkyl halide.  For the experiment we will perform, we will use β-naphthol (2-naphthol) as the alcohol and ethyliodide (iodoethane) as the alkyl halide to produce an ether, ethyl β-naphthyl ether, or 2-ethoxynaphthalene. (Naphthalene has two different types of carbon atoms that can undergo substitution. The top (and bottom) carbons are referred to as C-1 or the α-carbon. The other type of carbon [where the —OH is attached below] is the β-carbon or C-2.)

Aromatic alcohols, classified generally as phenols, function as relatively strong acidic alcohols because of resonance capabilities.  pK_a values for aromatic alcohols are typically in the 7-8 range.  When treated with sodium hydroxide, the alcoholic proton is titrated quantitatively to produce a stable anion (the salt is sodium phenoxide).  The phenoxide ion functions as a nucleophile in a reaction with an alkyl halide to generate the alkyl phenyl ether (and sodium halide).  The general reaction pathway is shown below.

For good yields of the ether (a S_N2 substitution product) to result, the alkyl halide must be a primary halide (e.g., methyl, ethyl or propyl halide, etc.).  If the alkyl halide were tertiary, the competing elimination reaction with the phenoxide ion reacting as a base would lead principally to elimination.  If the alkyl halide were secondary, both the elimination and desired subsitution reactions would occur with multiple products being produced, requiring extensive purification.

In the following reaction, sodium hydroxide reacts with the β-naphthol to produce the sodium salt of the β-naphthol.  The sodium salt reacts with ethyliodide (or methyliodide, if desired) to form ethyl β-naphthyl ether.  All of the species are brought into contact with each other by dissolving them in the solvent methanol (which is used only was solvent and not involved in the reaction).

There are two procedures listed, A & B; Your Instructor will determine which procedure is used.

Procedure A (Option #1: Without use of Phase Transfer Catalyst)

For safety considerations, introduce the reagents and initiate the reaction is the hood (in the order shown below).  The reaction will be performed in a 50-mL round-bottom flask equipped with a reflux condenser.  

To the 50-mL round-bottom flask, add the following reagents in the order shown.  Mix the contents by swirling after each addition of a new reagent.

• 10 mL of methanol
• 4.0 g (0.027 mol) of β-naphthol
• 4 mL (0.025 mol) of 25% NaOH solution (remember, NaOH is a catalyst, so it is not consumed during the reaction and is not a limiting reactant)
• 3.2 mL (0.040 mol) of ethyl iodide (1.936 g/mL)

Use caution and work in the hood until you are ready for reflux.  Add a few (~4-5) boiling stones, add the reflux condenser.  Reflux the mixture for 30 minutes onyour bench using the appropriate heating mantel.

Isolate and purify the product using the following procedure. 

Pour the reaction mixture quickly into 20 mL of cold water containing a little added ice.  

• At this point, you may, or may not observe the formation of solid material (evidence by the solution becoming cloudy).  If you observe solid material, then simply decant (pour) the water from the solid.  Be certain you know which layer is the water layer, and which layer is the organic layer.  Add an additional 5 mL of cold water to wash your product, and decant again.  
• Alternatively, if no solid is apparent (or even if there is) you can do the following (which is a safe way to isolate your ether). Add about 20-25 mL of diethyl ether to your mixture.  Transfer the entire mixture (aqueous and organic phases), to a separatory funnel.  Remove the lower aqueous phase and discard.  Collect the upper, organic (mostly diethyl ether) phase.  Heat this liquid in a hot water bath (do not heat your sample directly on top of the heating plate) until the ether is boiled away.  You should observe rapid boiling (gas bubbles produced) followed by a slowing of the boiling.  When the liquid appears not to be boiling vigorously, most of the diethyl ether will have been boiled away.  Proceed with the rest of the experiment as outlined below.

 Transfer the wet solid (or liquid which remains following remove of the diethyl ether) into a 125-mL Erlenmeyer flask.  Add about 40 mL of 95% ethanol.  Boil the solution for a few minutes to dissolve the ether (if it was a solid).  If some of the material does not dissolve, or if particulate matter is present, you will need to perform a hot filtration using a Büchner funnel.

Collect crystals by heating the alcohol-ether mixture by first reducing the volume to less than half of the original volume of ethanol (i.e., about 20 mL).  Crystals should form upon cooling.  If crystals do not form by the time the flask is cool enough to hold, the solution may be "seeded" by evaporating a little bit of it on a stirring the end of a stirring rod, and by using this rod, covered with "seed" crystals, to stir the solution and scratch the flask.  You may also facilitate crystal formation by gently swirling the cooled flask until crystals appear.  If crystals do not form you can facilitate crystal formation by decreasing the dissolving-potential of the solvent.  To do this, you can add small amounts of water to dilute the ethanol, and make the ether less soluble.  For example, the ether is very soluble in 95% ethanol but totally non-soluble in water.  By adding a small amount of water, you decrease the dissolving potential of the alcohol and force the ether out of solution.

Allow the crystals to form, cool in an ice bath, and then collect them by suction filtration.  Wash the crystals with two 3-mL portions of a cold ethanol solution. (Instead of using 95% ethanol, you could use a 50% ethanol-water mixture, which would likely be more effective for crystallization, since the ether is not soluble in water.)   Allow the crystals to dry until the next lab period.

If you did not produce crystals today, you will need to store your sample until the next lab period by labeling it properly and covering the container with Parafilm.

Analyze the solid ether product by determining the mass of crystals recovered, their melting point range, and their percent yield.  The melting point should be near 37^oC, as shown in the table below.  To ensure a more accurate melt point, let the temperature increase very slowly, so that there is time for the thermometer to adjust its temperature before the temperature increases more than a degree.  (The thermometer may take about 20-30 seconds to show the temperature in the melt apparatus, hence the need to increase temperature slowly.)

Procedure A (Option #2: With use of Phase Transfer Catalyst)

Experimental Procedure

To a 50-mL round-bottom flask, add the following reagents in the order shown.  Mix the contents by swirling after each addition of new reagent.  Conduct this process in a fume hood.

• 4.00 g (0.0277 mol) of β-naphthol (molar mass = 144.18 g/mol)
• 15 mL of chloroform
• 0.90 g (0.00277 mol) of tetra-n-butyl ammonium bromide (molar mass = 322.38 g/mol)
• 3.2 mL (0.040 mol) of ethyl iodide (1.936 g/mL)

Dissolve 2.22 g (0.0554 mol) sodium hydroxide in 15 mL of water and transfer this mixture to the 50-mL round-bottom flask.  Add 2-3 boiling stones and a magnetic stir bar to the 50-mL round-bottom flask.  Equip the flask with a condenser, heating mantle and magnetic stir plate device.  Gently stir the mixture and reflux the contents of the flask for 30 minutes. 

Allow the mixture to cool, pour the contents of the flask into a separatory funnel.  Add about 10 mL additional chloroform to the separatory funnel.  Separate the chloroform layer from the water layer (the chloroform layer is the bottom layer).   Return the chloroform layer to the separatory funnel and wash the chloroform layer 3 times with 15-20 ml of distilled water.  In order to conduct this wash process, the chloroform layer (bottom layer) will have to be removed from the separatory after each wash and then returned to the separatory funnel for the subsequent wash.  Discard the water wash solutions in the appropriate waste container.  Dry the chloroform layer over the minimum amount of anhydrous sodium sulfate and then carefully decant the chloroform layer into a clean, dry 50-mL round bottom flask.  Equip the flask with a simple distillation setup and carefully distill the chloroform from the product.  Collect the chloroform distillate and discard in an appropriate waste container.

Remove the distillation setup, add 35 mL of 95% ethanol to the flask and bring the contents of the flask to a gentle boil.  If the crude product does not dissolve completely, add and additional 5 mL of 95% ethanol and continue to gently boil the solution to digest the crude product.  If undissolved material still remains, add a second 5 mL portion of 95% ethanol and continue to gently boil the mixture.  If particulate material is evident at this point perform a hot filtration process using a warm Buchner funnel to remove any undissolved material from the ethanol solution.  Transfer the resulting ethanol solution to a 100-mL beaker, place the beaker on a hot plate and evaporate the ethanol to leave a solution volume of approximately 20 mL.  Remove the beaker from the hot plate and allow the solution to cool to room temperature to induce crystallization.  If crystals are not evident after cooling to room temperature, cool the beaker in an ice bath while gently scratching the bottom of the beaker with a glass stirring rod.  Collect the crystalline product by suction filtration and allow the solid product to dry on a watch glass until the next lab period.

Analyze the product by determining the melting point range, mass and percent yield.

Compound	MW	Amount Needed	mmol	mp	bp	Density	ηD
2-naphthol (β-naphthol)	144.17	4.0 g	27.7	122	286	1.174	---
iodoethane; ethyl iodide	155.966	3.2 mL (use pipettor)	39.6	-108	72	1.93	1.5133
methanol	32.04	10.0 mL		-98	64.6	0.791	1.3286
diethyl ether	74.1224	~20 mL		-116.3	34.6	0.7134	1.3526
2-ethoxynaphthalene	172.23	---		37	282	---	---

Product Synonyms:

• 2-Ethoxynaphthalene: β-naphthyl ethyl ether; Nerolin bromelia; Ethyl β-naphthyl ether; Ethyl 2-naphthyl ether; Naphthalene, 2-ethoxy-; 2-Ethoxynaphthalene;
• 2-Naphthol: 2-Naphthalenol; 2-Hydroxynaphthalene; beta-Naphthol; Beta-hydroxynaphthalene; Isonaphthol; 2-Naphthol; Hydroxynaphthalene; Naphthalenol; Naphthyl alcohol; Naphthyl hydroxide;
• Ethyliodide: Hydriodic ether; Iodoethane;
• Ether: Diethyl Oxide; Ether; Diethyl ether; Ethyl ether; 1,1'-Oxybisethane; ethyl oxide; pronarcol; Ethoxyethane; Ethyl Ether; DIETHYL ETHER (ETHYL ETHER);

QUESTIONS

1. Sodium hydroxide reacts with β-naphthol to form the sodium salt.  Can sodium ethoxide, the sodium salt of ethanol be formed the same way?  If not, what is an effective way to produce sodium ethoxide which can be used in organic reactions?
2. Explain why phenols, including the β-naphthol, which is used in the current experiment, would be acidic and why it easily reacts with base.
3. Why does the ether precipitate when the alcoholic reaction mixture is poured into water?
4. What else could have been used in place of ethyliodide to produce the same ether?  
5. Outline the S_N2 mechanism for this reaction.
6. Why is sodium hydroxide used in the smallest molar amount?
7. Explain the process of the "seeding" procedure.

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Copyright © Donald L. Robertson (Date last modified: 03/06/2007)