LAB 5 Materials

LAB 5 Materials - CHAPTER 5: SYNTHESIS OF ETHERS, 5.1....

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1 CHAPTER 5: SYNTHESIS OF ETHERS, 5.1. BACKGROUND, 5.1.1. Williamson Ether Synthesis This procedure was developed by Alexander Williamson in 1850 and involves the reaction of an alkoxide ion with a primary alkyl halide via an S N 2 reaction (Figure 5.1). This O-alkylation reaction is a popular approach to ethers. It should be noted that this reaction is very slow and often not feasible with secondary or tertiary halides, due to steric considerations. Sodium or potassium alkoxide ion is normally generated by reaction of an alcohol with the alkali metal. Since alkali metals react violently with phenols (due to their acidic character), alkali metal hydroxides or carbonates are employed. OH Na O Na Cl OH NaOH O O Na O Cl Mechanism: O Cl O S N 2 Figure 5.1. Williamson synthesis of ethers and the reaction mechanism. 5.1.2. The Mitsunobu reaction This procedure is regarded as one of the best methods for forming a heteroatom-carbon bond. The reaction, discovered by the Japanese chemist, Oyo Mitsunobu in 1967, is a highly stereoselective process occurring under mild conditions (essentially neutral at 0 o C to room temperature) in which an alcohol is converted into a variety of functional groups, such as an ether or an ester (see Chapter XX for esterification), using triphenylphosphine (TPP) and diethyl azodicarboxylate (DEAD). As shown in Figure 5.2, the reaction requires an acidic proton on the nucleophilic functionality and an alcohol as the electrophilic precursor. For example, a phenol (serving as a nucleophile, pKa<12) and an alcohol form an aryl-alkyl ether linkage. The reaction mechanism involves an initial nucleophilic attack of TPP to DEAD, producing a betaine intermediate A , which deprotonates the phenol to form the ion-pair B . The alcohol then reacts with the ion-pair to form the key oxyphosphonium ion C . This leaves an S N 2 attack of the phenolate ion on the intermediate C as the only productive pathway to form the desired ether and
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LAB 5 Materials - CHAPTER 5: SYNTHESIS OF ETHERS, 5.1....

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