Ethers nucleophilic substitution

The following section describes a versatile method for preparing either symmetri cal or unsymmetrical ethers that is based on the principles of bimolecular nucleophilic substitution... 

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... 

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... 

Nucleophilic Substitution Reactions. Many of the transformations reali2ed through Michael additions to quiaones can also be achieved usiag nucleophilic substitution chemistry. In some iastances the stereoselectivity can be markedly improved ia this fashion (100), eg, ia the reaction of ben2enethiol with esters (R = CH C O) and ethers (R = 3) 1,4-naphthoquiaones. 2-Bromo-5-acetyloxy-l,4-naphthoquiQone [77189-69-6J, R = Br, yields 75% of 2-thiophenyl-5-acetyloxy-l,4-naphthoquinone [71700-93-1], R = SC H. 3-Bromo-5-methoxy-1,4-naphthoquinone [69833-10-9], R = Br, yields 82% of 3-thiophenyl-5-methoxy-l,4-naphthoquinone [112740-62-2] R = SC H. ... 

Methyl bromide slowly hydrolyzes in water, forming methanol and hydrobromic acid. The bromine atom of methyl bromide is an excellent leaving group in nucleophilic substitution reactions and is displaced by a variety of nucleophiles. Thus methyl bromide is useful in a variety of methylation reactions, such as the syntheses of ethers, sulfides, esters, and amines. Tertiary amines are methylated by methyl bromide to form quaternary ammonium bromides, some of which are active as microbicides. 

Ring expansion of haloalkyloxiranes provides a simple two-step procedure for the preparation of azetidin-3-ols (Section 5.09.2.3.2(f)) which can be extended to include 3-substituted ethers and O-esters (79CRV331 p. 341). The availability of 3-hydroxyazetidines provides access to a variety of 3-substituted azetidines, including halogeno, amino and alkylthio derivatives, by further substitution reactions (Section 5.09.2.2.4). Photolysis of phenylacylamines has also found application in the formation of azetidin-3-ols (33). Not surprisingly, few 2-0-substituted azetidines are known. The 2-methoxyazetidine (57) has been produced by an internal displacement, where the internal amide ion is generated by nucleophilic addition to an imine. 

It was noted early by Smid and his coworkers that open-chained polyethylene glycol type compounds bind alkali metals much as the crowns do, but with considerably lower binding constants. This suggested that such materials could be substituted for crown ethers in phase transfer catalytic reactions where a larger amount of the more economical material could effect the transformation just as effectively as more expensive cyclic ethers. Knbchel and coworkers demonstrated the application of open-chained crown ether equivalents in 1975 . Recently, a number of applications have been published in which simple polyethylene glycols are substituted for crowns . These include nucleophilic substitution reactions, as well as solubilization of arenediazonium cations . Glymes have also been bound into polymer backbones for use as catalysts " " . 

A fluormated enol ether formed by the reaction of sodium ethoxide with chlorotnfluoroethylene is much less reactive than the starting fluoroolefin To replace the second fluorine atom, it is necessary to reflux the reaction mixture. The nucleophilic substitution proceeds by the addition-elimination mechanism [30] (equation 26). 

Unlike most ethers, epoxides (compounds in which the C—O—C unit forms a three-membered ring) are very reactive substances. The principles of nucleophilic substitution are important in understanding the preparation and properties of epoxides. 

Nucleophilic substitution has been used for the preparation of many thiophenes. For instance, 2-phenylthio-3,4-dinitro-5-piperidino-thiophene (155) has been prepared " through stepwise reaction of (150) with different nucleophiles. Nitrothienols and derivatives of them have been obtained from halogenated nitrothiophenes. " Allyl ethers have been prepared by the reaction of 5-chJoro-4-nitro-2-acetylthiophene, 3-nitro-2-chlorothiophene, and 2-nitro-3-bromothio-... 

Even polyalkoxy-s-triazines are quite prone to nucleophilic substitution. For example, 2,4,6-trimethoxy-s-triazine (320) is rapidly hydrolyzed (20°, dilute aqueous alkali) to the anion of 4,6-dimethoxy-s-triazin-2(l )-one (331). This reaction is undoubtedly an /S jvr-4r2 reaction and not an aliphatic dealkylation. The latter type occurs with anilines at much higher temperatures (150-200°) and with chloride ion in the reaction of non-basified alcohols with cyanuric chloride at reflux temperatures. The reported dealkylation with methoxide has been shown to be hydrolysis by traces of water present. Several analogous dealkylations by alkoxide ion, reported without evidence for the formation of the dialkyl ether, are all associated with the high reactivity of the alkoxy compounds which ai e, in fact, hydrolyzed by usually tolerable traces of water. Brown ... 

Comprehensive work in this field has been done by Slovak authors (98MI1, 95M1359, 96CCC269, 96CCC371, 97CCC99). They prepared 2-substituted (H, Me, Ph) 4-, 5-, 6-, and 7-nitrobenzoxazoles, which were then reduced to amines (not isolated) and subjected to subsequent nucleophilic substitution with activated enol ethers such as alkoxymethylene derivatives of malonic acid esters and nitrile, 3-oxobutanoic acid esters, pentanedione, or cyanoacetic acid esters to yield aminoethylenes 8. 

Nucleophilic substitution of the halogen atom of halogenomethylisoxazoles proceeds readily this reaction does not differ essentially from that of benzyl halides. One should note the successful hydrolysis of 4-chloromethyl- and 4-(chlorobenzyl)-isoxazoles by freshly precipitated lead oxide, a reagent seldom used in organic chemistry. Other halides, ethers, and esters of the isoxazole series have been obtained from 3- and 4-halogenomethylisoxazoles, and 3-chloro-methylisoxazole has been reported in the Arbuzov rearrangement. Panizzi has used dichloromethylisoxazole derivatives to synthesize isoxazole-3- and isoxazole-5-aldehydes/ ... 

Alkyl halides are encountered less frequently than their oxygen-containing relatives alcohols and ethers, but some of the kinds of reactions they undergo—nucleophilic substitutions and eliminations—are encountered frequently. Thus, alkyl halide chemistry acts as a relatively simple model for many mechanistically similar but structurally more complex reactions found in biornolecules. We ll begin in this chapter with a look at how to name and prepare alkyl halides, and we ll see several of their reactions. Then in the following chapter, we ll make a detailed study of the substitution and elimination reactions of alkyl halides—two of the most important and well-studied reaction types in organic chemistry. 

Acidic ether cleavages are typical nucleophilic substitution reactions, either SN1 or Sn2 depending on the structure of the substrate. Ethers with only primary and secondary alkyl groups react by an S 2 mechanism, in which or Br attacks the protonated ether at the less hindered site. This usually results in a selective cleavage into a single alcohol and a single alkyl halide. For example, ethyl isopropyl ether yields exclusively isopropyl alcohol and iodoethane on cleavage by HI because nucleophilic attack by iodide ion occurs at the less hindered primary site rather than at the more hindered secondary site. 

The most practical method for the preparation of polyfarylcnc ether)s employs nucleophilic aromatic substitution (SnAi). Although nucleophilic substitution can occur via four principal mechanisms,49 the most important mechanism utilized for the synthesis of poly(arylene etlier)s has been SnAt, in which activating groups are present on the aromatic ring (Scheme 6.10). 

The Ullman reaction has long been known as a method for the synthesis of aromatic ethers by the reaction of a phenol with an aromatic halide in the presence of a copper compound as a catalyst. It is a variation on the nucleophilic substitution reaction since a phenolic salt reacts with the halide. Nonactivated aromatic halides can be used in the synthesis of poly(arylene edier)s, dius providing a way of obtaining structures not available by the conventional nucleophilic route. The ease of halogen displacement was found to be the reverse of that observed for activated nucleophilic substitution reaction, that is, I > Br > Cl F. The polymerizations are conducted in benzophenone with a cuprous chloride-pyridine complex as a catalyst. Bromine compounds are the favored reactants.53,124 127 Poly(arylene ether)s have been prepared by Ullman coupling of bisphenols and... 

The method is quite useful for particularly active alkyl halides such as allylic, benzylic, and propargylic halides, and for a-halo ethers and esters, but is not very serviceable for ordinary primary and secondary halides. Tertiary halides do not give the reaction at all since, with respect to the halide, this is nucleophilic substitution and elimination predominates. The reaction can also be applied to activated aryl halides (such as 2,4-dinitrochlorobenzene see Chapter 13), to epoxides, " and to activated alkenes such as acrylonitrile. The latter is a Michael type reaction (p. 976) with respect to the alkene. 

There are two other approaches to enhancing reactivity in nucleophilic substitutions by exploiting solvation effects on reactivity the use of crown ethers as catalysts and the utilization of phase transfer conditions. The crown ethers are a family of cyclic polyethers, three examples of which are shown below. 

The cleavage of carbon-oxygen bonds in ethers or esters by nucleophilic substitution is frequently a useful synthetic transformation. 

Methoxyphenyl (PMP) ethers find occasional use as hydroxy protecting groups. Unlike benzylic groups, they cannot be made directly from the alcohol. Instead, the phenoxy group must be introduced by a nucleophilic substitution.185 Mitsunobu conditions are frequently used.186 The PMP group can be cleaved by oxidation with CAN. 

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