Williamson synthesis, crown ethers

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). 

Widman-Stoermer synthesis, 3, 43 Wild-fire toxin, 7, 249 Willardiine, synthesis, 3, 146 Willgerodt reaction thiophene synthesis by, 4, 883 Williamson reaction oxetane synthesis by, 7, 390-391 Withasomnine occurrence, 5, 302 Wittig reaction crown ethers and, 7, 759 Wittig-Homer reactions crown ethers and, 7, 759 Wolff rearrangement oxirenes in, 7, 120, 126... 

The preparation of crown ethers differs principally owing to the presence or absence of nitrogen. The preparation of all-oxygen heteromacrocycles has largely involved the Williamson ether synthesis. The preparation of aza-, diaza-, or triazacrowns has usually required the formation of cyclic amides, followed by reduction. The latter method applies to cryptands as well and has been used for that purpose since 1969. The methods are well known and shown in the lower panel of Figure 4. 

Reactions.- Crown lactones are reduced to the corresponding crown ether on reaction with LiAlH at 0°C. The procedure may allow the synthesis of crown ethers which are inaccessible by the Williamson ether synthesis. The reduction of 2,6-pyrido-18-crown-6 N-oxide by (CH CHCHgCH BH appears to involve a single electron transfer as the rate-determining step, followed by transfer of a... 

Abstract. Crown ethers derived from tartaric acid present a number of interesting features as receptor frameworks and offer a possibility of enhanced metal cation binding due to favorable electrostatic interactions. The synthesis of polycarboxylate crown ethers from tartaric acid is achieved by simple Williamson ether synthesis using thallous ethoxide or sodium hydride as base. Stability constants for the complexation of alkali metal and alkaline earth cations were determined by potentiometric titration. Complexation is dominated by electrostatic interactions but cooperative coordination of the cation by both the crown ether and a carboxylate group is essential to complex stability. Complexes are stable to pH 3 and the ligands can be used as simultaneous proton and metal ion buffers. The low extractibility of the complexes was applied in a membrane transport system which is a formal model of primary active transport. 

The central reaction is, of course, the Williamson ether synthesis. Early reports on the preparation of tartaric acid ethers [11], suggested that the base thallous ethoxide, (TlOEt), was essential to avoid epimerization of the chiral centers. The first syntheses thus utilized this base in dimethyformamide (DMF), and oligo-ethylenglycol diiodides for the preparation of di- and tetra-carboxylate crown ethers [4, 12]. More recently, we found that by strict control of stoichiometry, sodium hydride could be used successfully to displace tosylate without loss of chiral integrity [5]. Scheme 1 shows a recent synthesis of an 18-crown-6 hexaacid from three units of (H-)tartaric acid [13]. This route illustrates all the key features in the syntheses of polycarboxylate crown ethers. 

Potassium fluoride coated on alumina has been shown to be an effective and practical base for the usual Williamson-type synthesis of crown ethers from polyethylene glycols and polyethylene glycol ditosylates [equation (23)],giving yields comparable to standard methods. 

Introduction.—The ability of certain molecules, such as the macrocyclic crown ethers, e.g. 18-crown-6 (28), and the macrobicyclic cryptands, e.g. [2,2,2] cryptand (29), to form complexes with metal and ammonium cations has been extensively investigated in recent years. Since the original discovery by Pedersen, in 1967, of the crown group,some reviews and many papers have appeared on the syntheses and complexing properties of different classes of ligands, but it is not the intention here to go into detail concerning these aspects. Laboratory syntheses of the polyether class are dependent on the Williamson ether synthesis (Equation 11), but methods for production of commonly used compounds, such as (28), have been improved, and many representatives of both the crown and cryptand groups are now commercially available. 

Anhydrous sodium or potassium carbonates have been shown to act as efficient strong bases in solid-organic liquid two-phase systems in the presence of crown ethers this by-passes the requirement for concentrated aqueous hydroxide solutions in the equivalent liquid-liquid techniques. Among the reactions possible with this new method are the alkylation of active methylene compounds, the Williamson ether synthesis, and the Darzens reaction. 

Protection of Phenols. The reaction of MOMCl with a phenol under phase-transfer conditions works well to give phenolic MOM ethers and will selectivity protect a phenol in the presence of an alcohol. The more classical Williamson ether synthesis also provides excellent results, but may require the addition of a crown ether to enhance the nucleophilicity of the phenolate anion. As in the case of alcohol protection, alternatives using methylal have been developed for phenol protection which do not rely on the carcinogenic MOMCl.Phenolic silyl ethers can be converted directly to MOM ethers by reaction with TASF (Tris(dimethylamino)sulfonium Difluorotrimethyl-silicate) and MOMCl. ... 

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... 

An early synthesis of [18]crown-6 (1) involved the cyclization of hydroxychloride (30) via a Williamson ether synthesis. The yield was 2%. In an adaptation of this approach ethylene oxide was oligomerized in the presence of an alkali cation template. By varying the cation template from lithium to sodium to potassium the major macrocyclic product changed from [12]crown-4 to [15]crown-5 to [18]crown-6, albeit only in about 10% yield (76CC295). 

The syntheses of crown compounds invariably rely upon the Williamson ether synthesis, a dated but reliable reaction which is extemely useful in the synthesis of these medium-ring and large-ring compounds.7 The syntheses are usually not discussed in much detail in the literature, since the emphasis in the general area of supramolecular chemistry is on the properties of the target compounds, not on their preparation. It is frequently the case, however, that these apparently conventional syntheses are far from straightforward. 

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