Ethers Williamson, synthesis

Ether from the alkylation of alkoxides by alkyl halides. In order for reaction to go smoothly, the alkyl halides are preferred to be primary. Secondary halides work as well sometimes, but tertiary hahdes do not work at all because E2 elimination will be the predominant reaction pathway. 

Williamson, A. W. J. Chem. Soc. 1852, 4, 229-239. Alexander William Williamson (1824-1904) discovered this reaetion in 1850 at University College, London. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 286, Springer International Publishing Switzerland 2014 

Ether from the alkylation of alkoxides by alkyl halides. 

Hamada, Y. Kato, N. Kakamu, Y, Shioiri, T. Ghent. Pharnt. Bull. 1981,29,2246. 

Williamson synthesis of dialkyl ethers strong base 

Williamson synthesis of aryl ethers weak base 

R = 1°, 2° or 3° alkyl, allyl, benzyl Ar = aryl, heteroaryl M = Li, Na, K, Cs R = 1° or 2° alkyl, allyl, benzyl X = Cl, Br, I, OMs, OTs strong base alkali metals/liquid ammonia, metal hydrides, LHMDS, LDA weak base NaOH, KOH, K2CO3, CS2CO3 solvent usually 

In the case of most alkoxides and primary or secondary alkyl halides, the mechanism of the Williamson ether synthesis proceeds via an Sn2 process. When the alkyl halide Is secondary (R =H) with a given absolute configuration, the product ether will have a complete Inversion of configuration at that particular stererocenter. E.C. Ashby demonstrated, however, that the reaction between lithium alkoxides and alkyl Iodides proceeds via singleelectron transfer. 

The redox-active natural product (+)-methanophenazine (MP) is the first phenazine to be isolated from archea. This compound is able to mediate the electron transport between membrane-bound enzymes and was characterized as the first phenazine derivative involved in the electron transport of biological systems. The research team of U. Beifuss prepared this natural product by using the Williamson ether synthesis in the last step of the synthetic sequence. The etherification was conducted under phase-transfer conditions in a THF/water system in the presence of methyltrioctyl-ammonium chloride and using potassium hydroxide as a base. 

Alkoxides are excellent nucleophiles. This section describes their use in the most common method for the preparation of ethers. 

The simplest way to synthesize an ether is to have an alkoxide react with a primary halo-alkane or a sulfonate ester under typical Sn2 conditions (Chapter 6). This approach is known as the Williamson ether synthesis. The alcohol from which the alkoxide is derived can 

An example of a chemiluminescent molecule in nature is firefly luciferin. The base oxidation of this molecule furnishes a dioxacyclobutanone intermediate that decomposes in a manner analogous to that of 3,3,4,4-tetramethyl-l,2-dioxacyclobutane to give a complex heterocycle, carbon dioxide, and emitted light. 

Bioluminescence is extraordinarily efficient. For example, the firefly converts about 40% of the energy of the underlying chemical process into visible light. For your calibration, a normal light bulb is only 10% efficient, most of the (electric) energy being emitted as heat. 

CHAPTER 9 Further Reactions of Alcohols and the Chemistry of Ethers 

The Willgerodt reaction also works with hetaryl alkyl ketones, but often gives unsatisfactory yields. Yields generally decrease with increasing chain length of the alkyl group. 

Ethers by reaction of alkyl halides with alkoxides 

This reaction, which is named after W. Williamson, is the most important method for the synthesis of unsymmetrical ethers 3. For this purpose an alkoxide or phenoxide 1 is reacted with an alkyl halide 2 (with R = alkyl, allyl or benzyl). Symmetrical ethers can of course also be prepared by this route, but are accessible by other routes as well. 

For the classical Williamson synthesis an alcohol is initially reacted with sodium or potassium to give an alkoxide, e.g. 1. Alternatively an alkali hydroxide or amide may be used to deprotonate the alcohol. Phenols are more acidic, and can be converted to phenoxides by treatment with an alkali hydroxide or with potassium carbonate in acetone.  

In most cases the alkoxide or phenoxide 1 reacts with the alkyl halide 2 by a bimolecular nucleophilic substitution mechanism  

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Williamson ether synthesis Alkyl halides react with sodium or potassium alkoxides or phenox-ides to give ethers. 

A long standing method for the preparation of ethers is the Williamson ether synthesis Nucleophilic substitution of an alkyl halide by an alkoxide gives the carbon-oxygen bond of an ether... 

Preparation of ethers by the Williamson ether synthesis is most successful with methyl and primary alkyl halides... 

Write equations describing two different ways in which benzyl ethyl ether could be prepared by a Williamson ether synthesis J... 

Both reactants m the Williamson ether synthesis usually originate m alcohol pre cursors Sodium and potassium alkoxides are prepared by reaction of an alcohol with the appropriate metal and alkyl halides are most commonly made from alcohols by reaction with a hydrogen halide (Section 4 7) thionyl chloride (Section 4 13) or phosphorus tri bromide (Section 4 13) Alternatively alkyl p toluenesulfonates may be used m place of alkyl halides alkyl p toluenesulfonates are also prepared from alcohols as their imme diate precursors (Section 8 14)... 

Next in what amounts to an intramolecular Williamson ether synthesis the alkoxide oxygen attacks the carbon that bears the halide leaving group giving an epoxide As m other nucleophilic substitutions the nucleophile approaches carbon from the side oppo site the bond to the leaving group... 

The Williamson ether synthesis (Sec tion 16 6) An alkoxide ion displaces a halide or similar leaving group in an Sn2 reaction The alkyl halide cannot be one that is prone to elimination and so this reaction is limited to methyl and primary alkyl halides There is no limitation on the alkoxide ion that can be used... 

Base promoted cyclization of vicinal halohydrms (Section 16 10) This reaction is an intramolecu lar version of the Williamson ether synthesis The alcohol function of a vicinal halohydrin is con verted to its conjugate base which then displa ces halide from the adjacent carbon to give an epoxide... 

Outline the steps in the preparation of each of the constitutionally isomeric ethers of molec ular formula C4H10O starting with the appropriate alcohols Use the Williamson ether synthesis as your key reaction... 

Ethers are formed under conditions of the Williamson ether synthesis Methyl ethers of carbohydrates are efficiently prepared by alkylation with methyl iodide m the presence of silver oxide... 

Alkylation (Section 25 22) Alkyl halides react with carbohydrates to form ethers at the available hydroxyl groups An application of the Williamson ether synthesis to carbohydrates... 

Weak acid (Section 1 16) An acid that is weaker than 1130" Weak base (Section 1 16) A base that is weaker than HO Williamson ether synthesis (Section 16 6) Method for the preparation of ethers involving an Sfj2 reaction between an alkoxide ion and a primary alkyl halide... 

In early work, vinyl chloride had been heated with stoichiometric amounts of alkaU alkoxides in excess alcohol as solvent, giving vinyl ethers as products (210). Supposedly this involved a Williamson ether synthesis, where alkaU alkoxide and organic haUde gave an ether and alkaU haUde. However, it was observed that small amounts of acetylene were formed by dehydrohalogenation of vinyl chloride, and that this acetylene was consumed as the reaction proceeded. Hence acetylene was substituted for vinyl chloride and only catalytic amounts of alkaU were used. Vinylation proceeded readily with high yields (211). 

The most versatile method of preparing ethers is the Williamson ether synthesis, particularly in the preparation of unsymmetrical alkyl ethers (12,13). The reaction of sodium alcoholates with halogen derivatives of hydrocarbons gives the ethers ... 

WILLIAMSON Ether synthesis Synthesis of ethers from alcoholates with alkyl halides... 

Picolyl ethers are prepared from their chlorides by a Williamson ether synthesis (68-83% yield). Some selectivity for primary versus secondary alcohols can be achieved (ratios = 4.3-4.6 1). They are cleaved electrolytically ( — 1.4 V, 0.5 M HBF4, MeOH, 70% yield). Since picolyl chlorides are unstable as the free base, they must be generated from the hydrochloride prior to use. These derivatives are relatively stable to acid (CF3CO2H, HF/anisole). Cleavage can also be effected by hydrogenolysis in acetic acid. ... 

Many of the crown ether syntheses with which we are concerned in this book are one form or another of the Williamson ether synthesis. Although the simplest example of such a reaction would involve an co-haloethylene glycol oligomer which undergoes intramolecular cyclization, it is more common for two new bonds to be formed in crown syntheses. An early example of the formation of a crown by a double-Williamson can be found in Dale s synthesis of 18-crown-6. The rather obvious chemical steps are shown in Eq. (2.1). 

Reinhoudt, de Jong and Tomassen have explored the use of metallic fluorides as bases in the Williamson ether synthesis of crowns. They found that the efficacy order for the metal cations they examined was Cs" > Rb > > Na Li . This order was... 

Macrocycles have been prepared by formation of macrocyclic imines as well as by using variations of the Williamson ether synthesis ". Typically, a diamine or dialdehyde is treated with its counterpart to yield the Schiff s base. The saturated macrocycle may then be obtained by simple reduction, using sodium borohydride, for example. The cyclization may be metal-ion templated. In the special case of the all-nitrogen macrd-cycle, 15, the condensation of diamine with glyoxal shown in Eq. (4.14), was unsuccess-ful ... 

Picolyl ethers are prepared from their chlorides by a Williamson ether synthesis (68-83% yield). Some selectivity for primary vs. secondary alcohols can be achieved (ratios = 4.3-4.6 1). Picolyl ethers are cleaved electrolytically ( —1.4 V,... 

A variant of the Williamson ether synthesis uses thallium alkoxides. The higher reactivity of these can be of advantage in the synthesis of ethers from diols, triols and hydroxy carboxylic acids, as well as from secondary and tertiary alcohols on the other hand however thallium compounds are highly toxic. 

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