Synthesis of ethers

Production of ethylene oxide by the cata lytic oxidation of ethylene. 

Althou MTBE is nerated as a by-product of propylene oxide production [125], direct synthesis by acid-catalyzed addition of methanol to isobutylene is necessary to meet the rapid increase in worldwide MTBE demand. Worldwide capacity of MTBE is expected to double by 1995 from the 1992 level of 377,000 bbl/day [125,126], and much of this increased capacity is expected to come from new plants and MTBE expansions [126]. 

Commercial MTBE (and TAME) synthesis occurs at about 1.5 MPa and 100°C in the liquid phase over an acid resin catalyst that is based on the sulfonic acid group -SO H. The synthesis reaction is sli tly exothermic and limited by equilibrium under the conditions of the commercial operation  

The reaction mechanism and kinetics of the MTBE synthesis from methanol and isobutylene have been studied over the commercial Amberlyst 15 cation-exchange resin catalyst. An activation energy of 71.2 kJ/mol was reported by Ancillotti et aL [127] for the forward reaction, whereas Gicquel and Torek [128] reported a value of 82.0 kJ/moL For the reverse reaction an activation ener of 122.6 kJ/mol has been reported [128]. The kinetics of the reaction are very dependent on the olefin and alcohol concentration. Ancillotti et aL [129] showed that the initial rate of synthesis is zero order in methanol at methanol-isobutylene ratios 1. Most commercial processes operate at close to the stoichiometric ratio, and the rate is first order in isobutylene under these conditions. Ancillotti et aL [129] suggested that the effect of alcohol-olefin ratio can be e q)lained in terms of the equilibrium reaction 

The kinetics are consistent with an ionic mechanism wherein the rate-determining step is the protonation of the olefin by the solvated proton. At lower alcohol-olefin ratios ( 1), the order of reaction is negative in the alcohol, reaction (43) is shifted to the left, and the olefin is protonated directly by the sulfonic acid group of the resin. A Langmuir-Hinshelwood model of the kinetics was also described by Gicquel and Torek [128] for relatively hi methanol concentrations. 

Commercial MTBE (and TAME) processes are very similar and based on the acid-catalyzed addition of methanol to isobutylene. The reactor effluent is fractionated in various stages to recover MTBE, methanol for recycle, and unreacted C4 hydrocarbons present in the feed. The three different designs of the commercial processes reflect different approaches to control the heat gen- 

Intramolecular dehydration (alkene formation) and intermolecular dehydration are competitive processes but selective ether synthesis is possible by applying appropriate catalysts under suitable reaction conditions. 

Characteristic examples of the dehydration of primary alcohols are collected in Table 1. Kaolinite containing alumina [67], aluminas, modified aluminas [68,69], silica-aluminas [70] and AIPO4 [26] have also been studied. Ether formation was found to be favored by a high concentration of sites of intermediate or weak acidity. 

Nafion-H is a particularly efficient and recyclable catalyst. Surprisingly, even methyl isobutyl ether is formed selectively in the reaction of methanol and 2-methyl-1-propanol over Nafion-H, ruling out the involvement of a carbocationic intermediate [71]. 

When secondary alcohols are reacted reaction conditions (choice and quantity of catalyst, temperature) are even more important, because of more competitive alkene formation and the unfavorable steric effect. Nafion-H has exceptionally high activity in the formation of ethers from cyclohexanol and ejco-norborneol (91 % and 99% yield, respectively) [66]. This is in sharp contrast with Al -ex-changed bentonite which gave dicyclohexyl ether in mere 15 % yield [72]. 

The pore structure of the catalyst has been shown to have a large influence in the etherification of 1-phenyl-1-ethanol [73] the favorable performance of tita- 

Alcohols can dehydrate to form alkenes. We studied this in Sections 7.7 and 7.8. Primary alcohols can also dehydrate to form ethers  

Dehydration to an ether usually takes place at a lower temperature than dehydration to the alkene, and dehydration to the ether can be aided by distilling the ether as it is formed. Diethyl ether is made commercially by dehydration of ethanol. Diethyl ether is the predominant product at 140°C ethene is the major product at 180°C  

The formation of the ether occurs by an Sn2 mechanism with one molecule of the alcohol acting as the nucleophile and another protonated molecule of the alcohol acting as the substrate (see Section 11.5). 

This is an acid-base reaction in which the alcohol accepts a proton from the sulfuric acid. 

Another molecule of the alcohol acts as a nucleophile and attacks the protonated alcohol in an S 2 reaction. 

Diethyl ether and other simple symmetrical ethers are prepared industrially by the sulfuric acid-catalyzed reaction of alcohols. The reaction occurs by Sn2 displacement of water from a protonated ethanol molecule by the oxygen atom of a second ethanol. Unfortunately, the method is limited to use with primary alcohols because secondary and tertiary alcohols dehydrate by an El mechanism to yield alkenes (Section 17.6). 

The most generally useful method of preparing ethers is by the Williamson ether synthesis, in which an alkoxide ion reacts with a primary alkyl halide or tosylate in an Sn2 reaction. As we saw earlier in Section 17.2, the alkoxide ion is normally prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH. 

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A useful variation of the Williamson synthesis involves silver oxide, Ag20, as a mild base rather than NaH. Under these conditions, the free alcohol reacts directly with alkyl halide, so there is no need to preform the metal alkoxide intermediate. Sugars react particularly well glucose, for example, reacts with excess iodomethane in the presence of Ag20 to generate a pentaether in 85% yield. 

Because the Williamson synthesis is an Sn2 reaction, it is subject to all the usual constraints, as discussed in Section 11.3. Primary halides and tosylates work best because competitive E2 elimination can occur with more hindered substrates. Unsymmetrical ethers should therefore be synthesized by reaction between the more hindered alkoxide partner and less hindered halide partner rather than vice versa. For example, fert-butyl methyl ether, a substance used in the 1990s as an octane booster in gasoline, is best prepared by reaction of tert-butoxide ion with iodomethane rather than by reaction of methoxide ion with 2-chloro-2-methylpropane. 

Alexander W. Williamson (1824-1904) was born in London, England, and received his Ph.D. at the University of Giessen in 1846. His ability to work in the laboratory was hampered by a childhood injury that caused the ioss of an arm. From 1849 until 1887, he was professor of chemistry at University College, London. 

Why do you suppose only symmetrical ethers are prepared by the sulfuric acid-catalyzed dehydration procedure What producl(s) would you expect if ethanol and 1-propanol were allowed to react together In what ratio would the products be formed if the two alcohols were of equal reactivity  

One of the most useful applications of phase transfer catalysis in nucleophilic substitution has been in the Williamson ether synthesis. The reaction of an alkoxide anion with an alkyl halide or sulfonate to give either symmetrical or unsymmetrical ethers (depending on reactants) shows significant improvement in convenience, reaction rate, and yield when conducted under phase transfer catalytic conditions. 

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When applied to the synthesis of ethers the reaction is effective only with primary alcohols Elimination to form alkenes predominates with secondary and tertiary alcohols Diethyl ether is prepared on an industrial scale by heating ethanol with sulfuric acid at 140°C At higher temperatures elimination predominates and ethylene is the major product A mechanism for the formation of diethyl ether is outlined m Figure 15 3 The individual steps of this mechanism are analogous to those seen earlier Nucleophilic attack on a protonated alcohol was encountered m the reaction of primary alcohols with hydrogen halides (Section 4 12) and the nucleophilic properties of alcohols were dis cussed m the context of solvolysis reactions (Section 8 7) Both the first and the last steps are proton transfer reactions between oxygens... 

The conversion of chlorohydrins into epoxides by the action of base is an adaptation of the Williamson synthesis of ethers. In the presence of hydroxide ion, a small proportion of the alcohol exists as alkoxide, which displaces the chloride ion from the adjacent carbon atom to produce a cycHc ether (2). 

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

Williamson reaction is the synthesis of ethers by action of heat on a mixture of alkyl haldie and sodium or potassium alkoxide... 

Contents Introduction and Principles. - The Reaction of Dichlorocarbene With Olefins. - Reactions of Dichlorocarbene With Non-Olefinic Substrates. -Dibromocarbene and Other Carbenes. - Synthesis of Ethers. - Synthesis of Esters. - Reactions of Cyanide Ion. - Reactions of Superoxide Ions. - Reactions of Other Nucleophiles. - Alkylation Reactions. - Oxidation Reactions. - Reduction Techniques. - Preparation and Reactions of Sulfur Containing Substrates. -Ylids. - Altered Reactivity. - Addendum Recent Developments in Phase Transfer Catalysis. 

When applied to the synthesis of ethers, the reaction is effective only with primary alcohols. Elimination to form alkenes predominates with secondary and tertiary alcohols. 

In addition to its uses in photography and medicine, iodine and its compounds have been much exploited in volumetric analysis (iodometry and iodimetry, p. 864). Organoiodine compounds have also played a notable part in the development of synthetic organic chemistry, being the first compounds used in A. W. von Hofmann s alkylation of amines (1850), A. W. Williamson s synthesis of ethers (1851), A. Wurtz s coupling reactions (1855) and V. Grignard s reagents (1900). 

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. 

Treatment of a thiol with a base, such as NaH, gives the corresponding thiolate ion (RS-), which undergoes reaction with a primary or secondary alkyl halide to give a sulfide. The reaction occurs by an Sn2 mechanism, analogous to the Williamson synthesis of ethers (Section 18.2). Thiolate anions are among... 

Synthesis of ethers (Section 18.2) (a) Williamson ether synthesis... 

There are two important methods for the synthesis of ether carboxylates from ethoxylated fatty alcohols ... 

Choose starting materials for a one-step synthesis of ether (10) saying why you chose these particular compounds,... 

The enzymes in peroxisomes do not attack shorter-chain fatty acids the P-oxidation sequence ends at oc-tanoyl-CoA. Octanoyl and acetyl groups are both further oxidized in mitochondria. Another role of peroxisomal P-oxidation is to shorten the side chain of cholesterol in bile acid formation (Chapter 26). Peroxisomes also take part in the synthesis of ether glycerolipids (Chapter 24), cholesterol, and dolichol (Figure 26-2). 

The original medicinal chemistry synthesis of ether 18 involved reaction of alcohol 10 with racemic imidate 17 in the presence of a catalytic amount of TfOH and furnished an approximately 1.1 1 mixture of 18 19 (Scheme 7.3) [1], We thought it worthwhile to reinvestigate this reaction with chiral imidate 67 in an effort to explore the diastereoselectivity of the etherification. 

Tab. 5.5 Synthesis of ethers under MW + PTC conditions (domestic oven, 560 W).

The application of phase-transfer catalysis to the Williamson synthesis of ethers has been exploited widely and is far superior to any classical method for the synthesis of aliphatic ethers. Probably the first example of the use of a quaternary ammonium salt to promote a nucleophilic substitution reaction is the formation of a benzyl ether using a stoichiometric amount of tetraethylammonium hydroxide [1]. Starks mentions the potential value of the quaternary ammonium catalyst for Williamson synthesis of ethers [2] and its versatility in the synthesis of methyl ethers and other alkyl ethers was soon established [3-5]. The procedure has considerable advantages over the classical Williamson synthesis both in reaction time and yields and is certainly more convenient than the use of diazomethane for the preparation of methyl ethers. Under liquidrliquid two-phase conditions, tertiary and secondary alcohols react less readily than do primary alcohols, and secondary alkyl halides tend to be ineffective. However, reactions which one might expect to be sterically inhibited are successful under phase-transfer catalytic conditions [e.g. 6]. Microwave irradiation and solidrliquid phase-transfer catalytic conditions reduce reaction times considerably [7]. 

Williamson synthesis org chem The synthesis of ethers utilizing an alkyl iodide and sodium alcoholate. wil-yom-san sin-tha-sas )... 

Uses. Reactive diluent for epoxy resins stabilizer for organic compounds chemical intermediate for synthesis of ethers and esters... 

Bennie, L. et al.. Oligomeric flavanoids. Part 32. Structure and synthesis of ether-linked proter-acacinidin and promelacacinidin proanthocyanidins from Acacia caffra. Phytochemistry, 53, 785, 2000. 

Synthesis of ether-linked gemini aromatic epoxides. 

Valerio, R. M. Bray, A. M. Patsiouras, H. Multipin Solid Phase Synthesis of Ethers Using Modified Mitsunobu Chemistry, Tetrahedron Lett. 1996,37, 3019. 

An efficient synthesis of ethers involves hydrozirconation of thioketones with hydrochlorobis(cyclopentadienyl)zirconium [251]. 

The so-called Williamson synthesis of ethers is by far the most important ether synthesis because of its versatility it can be used to make unsymmetrical ethers as well as symmetrical ethers, and aryl alkyl ethers as well as dialkyl ethers. These reactions involve the nucleophilic substitution of alkoxide ion or phenoxide ion for halide (equation 70).26°... 

Cu(OR)2 were proposed as catalysts for the Et2S oxidation in oil [1068], for the oxidative polymerization [60], for the reversible fixation of CO and C02 with formation of alkylcarbonates [1381, 1602], and also as alkoxylating agents in the reactions with RHal for the synthesis of ethers [1741], Reduction of the copper glycerate with metallic A1 was used for the preparation of high-purity copper powders with 0.01 to 0.05 m particle size, which is a highly active catalyst [715]. 

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