Chemistry 335A
Preparation of an Ether:
The Williamson Synthesis
The Williamson Synthesis
Unhindered alkyl halides (RX) undergo backside (SN2) attack by nucleophiles. In this type of reaction the nucleophile replaces the halide ion as shown below (Eq. 1).
The abbreviation SN2 for the mechanism of these reactions stands for substitution, nucleophilic, bimolecular,and the rate law for the reaction is: rate= [RX] [Nu:]. If the nucleophile in the reaction is an alkoxide or phenoxide ion, the product is an ether, and the reaction is called the Williamson ether synthesis (Eq. 2).
where R' = alkyl or aryl. When the nucleophile is an alkoxide ion such as ethoxide, CH3CH2O:-, the reaction must be carried out in an anhydrous solvent since the strongly basic alkoxide ions react with water in an acid-base reaction as shown below (Eq. 3).
In contrast, when much less basic phenoxide ions are used to make an "aromatic" ether, as shown below in (Eq. 4), water an be used as the solvent for the reaction.
Unfortunately, while ionic phenoxide ions are soluble in water, the alkyl halides are not. One solution is to use a polar organic solvent like acetone as the solvent, but reaction rates can be slow and yields are not so good. Another solution to this problem is to use water as the solvent along with a so-called "phase transfer" catalyst such as tetra-n-butylammonium iodide. In solution some tetra-n-butylammonium phenoxide is present. Even though this material is ionic, it is still soluble in the organic phase of the reaction mixture where the SN2 reaction can occur. For a full discussion of phase transfer catalysis see pp. 391-394 in your lecture textbook, Organic Chemistry by Brown.
Procedure:
Synthesis
Place 10 mL of the labeled 5M phenoxide or substituted phenoxide solution (0.05mole) in a 50 mL round-bottomed flask. Add 0.5 g of phase transfer catalyst followed by 0.05 mole of your assigned alkyl halide. A separate layer should be present at this point in the procedure. Equip the flask a magnetic stirring bar and a reflux condenser and place a heating mantle under the flask. After determining that cold water in flowing through the condenser and that vigororous stirring in occuring heat the contents of the flask so that a gentle reflux occurs for 45 minutes
Isolation and Purification
Cool the flask in an ice bath and pour its contents into your separatory funnel. Add 20ml of ether to the flask, and after gentle swirling remove the aqueous layer. Washing the organic layer successively with 10 ml of 5% NaOH and 10ml of water. Place the organic layer in a small Erlenmeyer flask and add drying agent (Na2SO4 or MgSO4). After several minutes decant the clear, dried organic layer into your cleaned 50 mL round-bottomed flask. To improve your yield, rinse the drying agent with about 5 mL of diethyl ether and add this to your product.
Add a couple of boiling chips to this flask and set up the small scale distillation shown in the illustration at the end of this handout. Collect the initial low boiling forerun and then in a new receiver collect the product at its expected boiling point in a preweighed round-bottomed flask. Be sure not to distill to complete dryness.
Reweigh the collection flask to determine your yield and then collect the usual analytical data: glpc, ir, nmr, refractive index, and gcms
Turn in your remaining product in a small vial labeled with your name and the name of your product.
Turn in your product in a small vial labeled with your name and the name of your product.
kh 20 July 00