Alkyl halides treatment with alkoxide

Alcohols undergo many reactions and can be converted into many other functional groups. They can be dehydrated to give alkenes by treatment with POCI3 and can be transformed into alkyl halides by treatment with PBr3 or SOCU- Furthermore, alcohols are weakly acidic (p/C, — 16-18) and react with strong bases and with alkali metals to form alkoxide anions, which are used frequently in organic synthesis. 

The reaction of acceptor-substituted carbene complexes with alcohols to yield ethers is a valuable alternative to other etherification reactions [1152,1209-1211], This reaction generally proceeds faster than cyclopropanation [1176], As in other transformations with electrophilic carbene complexes, the reaction conditions are mild and well-suited to base- or acid-sensitive substrates [1212], As an illustrative example, Experimental Procedure 4.2.4 describes the carbene-mediated etherification of a serine derivative. This type of substrate is very difficult to etherify under basic conditions (e.g. NaH, alkyl halide [1213]), because of an intramolecular hydrogen-bond between the nitrogen-bound hydrogen and the hydroxy group. Further, upon treatment with bases serine ethers readily eliminate alkoxide to give acrylates. With the aid of electrophilic carbene complexes, however, acceptable yields of 0-alkylated serine derivatives can be obtained. 

Williamson ether synthesis (Section 18.2) a method for preparing an ether by treatment of a primary alkyl halide with an alkoxide ion. 

Alcohols undergo a great ntany rea-ctions. Tlie,v can be dehydrated treatment with POCl , und. c,yn be trnnsformed into alkyl halides by treat ment with PBrj or SOCtj Furthermore, aloohoU are weakly aadie alkoxide anions, which arc used frequently in organic ayolheais. 

The Williamson reaction, discovered in 1850, is still the best general method for the preparation of unsymmetrical or symmetrical ethers.The reaction can also be carried out with aromatic R, although C-alkylation is sometimes a side reaction (see p. 515). The normal method involves treatment of the halide with alkoxide or aroxide ion prepared from an alcohol or phenol, although methylation using dimethyl carbonate has been reported. It is also possible to mix the halide and alcohol or phenol directly with CS2CO3 in acetonitrile, or with solid KOH in Me2SO. The reaction can also be carried out in a dry medium,on zeolite-or neat or in solvents using microwave irradiation. Williamson ether synthesis in ionic liquids has also been reported. The reaction is not successful for tertiary R (because of elimination), and low yields are often obtained with secondary R. Mono-ethers can be formed from diols and alkyl halides. Many other... 

The Williamson synthesis involves nucleophilic substitution of alkoxide ion or phenoxide ion for halide ion it is strictly analogous to the preparation of alcohols by treatment of alkyl halides with aqueous hydroxide (Sec. 15.7). Aryl halides cannot in general be used, because of their low reactivity toward nucleophilic substitution. 

Carbon disulfide is a valuable synthon (see Chapter 9, p. 147) which can be used for the synthesis of thiocarbonic acid derivatives. Thus, carbon disulfide reacts with ammonium polysulfide or hydrogen sulfide to give trithiocarbonic acid (70) or symmetrical esters (73) after reaction with an alkyl halide. With alkoxides or thiolates, carbon disulfide forms xanthates (77) or S-alkyl trithiocarbonates the latter by further treatment with alkyl, acyl or diazonium halides affords the derivatives (74)-(76) (Scheme 39). 

Williamson reaction The formation of an ether by the treatment of an alkyl halide with an alkoxide anion. Gem-dihalides react with alkoxides to give acetals, while 1,1,1-trihalides give ortho esters. 

Williams and McClymont described detailed studies of the alkylation and acylation of 5-(l,3-dithian-2-yl)oxazole 932. The authors showed from deuterium incorporation studies that sequential deprotonation of 932 occurred first at C(2) and then at the dithiane carbon atom. Thus treatment of 932 with excess LiHMDS followed by an alkylating agent afforded exclusively the side chain alkyl analogues 933 (Scheme 1.249, Table 1.67). Reactive electrophiles, e.g., CH3I and TMSCl afforded complex mixtures of C- and O-alkylated products derived from the acyclic isocyanovinyllithium alkoxides 938a and 938b (discussed below), whereas secondary alkyl halides were unreactive. 

Higher alkynes can be synthesized fhom acetylene by reacting with NaNH followed by treatment with the appropriate alkyl halide.Terminal alkynes can be deprotonated using strong bases such as sodium amide. Hydroxides or alkoxides are not strong enough to deprotonate an acetylenic hydrogen. 

Most important for the laboratory synthesis of unsymmetric ethers is the Williamson synthesis, named after the British chemist who devised it. This method has two steps, both of which we have already discussed. In the first step, an alcohol is converted to its alkoxide by treatment with a reactive metal (sodium or potassium) or metal hydride (review eqs. 7.12 and 7.13). In the second step, an 5 2 displacement is carried out between the alkoxide and an alkyl halide (see Table 6.1, entry 2). The Williamson synthesis is summarized by the general equations... 

The sodium salt of the methylsulphinyl carbanion, Me SO CH2 Na+, has simple uses in synthesis, such as converting alcohols into alkoxides, for the synthesis of ethers by alkylation with an alkyl halide, or for synthesis of xanthates by successive treatment with CSa and an alkyl halide. The method is useful for reactions with tertiary alcohols. 

Ethers are frequently prepared via the Williamson ether synthesis, which involves the reaction of an alkyl halide electrophile (RX) with an alkoxide nucleophile (R O ). As usual, the Sn2 backside attack is sensitive to sterics, and the E2 elimination reaction is expected to compete here since alkoxides are strong bases. The Sn2 substitution can be expected to give good yields of the ether if the halide is on a methyl, primary, allylic, or benzylic carbon. Simple alkoxides may be commercially available otherwise, the alkoxide can be prepared from the corresponding alcohol by treatment with a strong base (NaH) or a metal (Na or K). 

Alkoxides are readily formed from partially substituted polyols and sugars by treatment with sodium naphthalenide 19) in 1,2-dimethoxy-ethane solution and subsequent reaction with alkyl halides then produces ethers 20). The reaction sequence is simple to apply, and the method deserves further investigation. 

Oligosilanyl halides are also very abundant and their treatment as a separate compound class would thus be too exhaustive. Silyl halides are of major importance for the generation of numerous silicon species. By reaction with nucleophiles including lithium alkyls, silyl anions, amines, amides, alcohols, and alkoxides, Si-X bonds are easily formed. They also serve as starting materials for Si-Si bond formation by Wurtz coupling or for the generation of unsaturated compounds such as disilenes, disilynes, or silylenes. 

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