Halides, alkyl, reaction with alkoxides

Alkyl halides readily undergo nucleophilic substitution reactions with alkoxides to give ethers (the Williamson ether synthesis). In this case, the reaction would be an Intramolecular... 

Higher alcohols (> C3) react comparatively slowly with sodium because of the slight solubility of the sodium alkoxide in the alcohol a large excess (say, 8 mols) is therefore employed. The mixed ether is distilled off, and the process (formation of alkoxide and its reaction with the alkyl halide) may be repeated several times. The excess of alcohol can be recovered. cj/cloAliphatic alcohols form sodio compounds with difficulty if small pieces... 

Recall from Section 8 13 that the major pathway for reaction of alkoxide ions with secondary alkyl halides IS E2 not Sn2... 

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)... 

Ethers by reaction of alkyl halides with alkoxides... 

The E2 reaction (for elimination, bimolecular) occurs when an alkyl halide is treated with a strong base, such as hydroxide ion or alkoxide ion (RO-). It is the most commonly occurring pathway for elimination and can be formulated as shown in Figure 11.17. 

Ethers can often be prepared by SN2 reaction of alkoxide ions, RO-. with alkyl halides. Suppose you wanted to prepare cyclohexyl methyl ether. Which of the two possible routes shown below would you choose Explain. 

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 alkoxide ion reacts with the substrate in an SN2 reaction, with the resulting formation of the ether. The substrate must bear a good leaving group. Typical substrates are alkyl halides, alkyl sulfonates, and dialkyl sulfates, i.e. 

Alkoxylation. A reaction of alkoxides with an alkyl halide to produce ethers, (ex R-O-Na + R Cl = R-O-R + NaCl). 

Alkyl halides undergo Sn2 reactions with a variety of nucleophiles, e.g. metal hydroxides (NaOH or KOH), metal alkoxides (NaOR or KOR) or metal cyanides (NaCN or KCN), to produce alcohols, ethers or nitriles, respectively. They react with metal amides (NaNH2) or NH3, 1° amines and 2° amines to give 1°, 2° or 3° amines, respectively. Alkyl halides react with metal acetylides (R C=CNa), metal azides (NaN3) and metal carboxylate (R C02Na) to produce internal alkynes, azides and esters, respectively. Most of these transformations are limited to primary alkyl halides (see Section 5.5.2). Higher alkyl halides tend to react via elimination. 

We have already learnt that alkyl halides react with alcohols and metal hydroxide (NaOH or KOH) to give ethers and alcohols, respectively. Depending on the alkyl halides and the reaction conditions, both S l and Sn2 reactions can occur. Alkyl halides undergo a variety of transformation through Sn2 reactions with a wide range of nucleophiles (alkoxides, cyanides, acetylides, alkynides, amides and carboxylates) to produce other functional groups. 

Reaction between alkoxides or arox-ides and alkyl halides (Williamson) 0-14 Reaction between alkoxides or arox-ides and inorganic esters 0-15 Alkylation of alcohols or phenols with diazo compounds 0-16 Dehydration of alcohols 0-17 Transetherification 0-19 Alkylation of alcohols with onium salts... 

In fact, the reaction of alkoxides with alkyl halides or alkyl sulfates is an important general method for the preparation of ethers, and is known as the Williamson synthesis. Complications can occur because the increase of nucleo-philicity associated with the conversion of an alcohol to an alkoxide ion always is accompanied by an even greater increase in eliminating power by the E2 mechanism. The reaction of an alkyl halide with alkoxide then may be one of elimination rather than substitution, depending on the temperature, the structure of the halide, and the alkoxide (Section 8-8). For example, if we wish to prepare isopropyl methyl ether, better yields would be obtained if we were to... 

The selection of reagents is governed by availability, cost, and, more importantly, the possible intrusion of side reactions. Thus in the above example, the action of the strongly basic ethoxide ion on t-butyl bromide would give rise to extensive alkene formation on the other hand little or no elimination would occur by the alternative reaction route. In general therefore, secondary or tertiary alkyl groups can only be incorporated into ethers by the Williamson synthesis by way of the corresponding alkoxide ions in reaction with a primary halide. 

Isolation of the intermediate xanthate salts in the preparation of the xanthate esters is not essential. The formation of the latter may be achieved, in one step, by converting the alcohol into the corresponding alkoxide by reaction with a potassium derivative of a tertiary alcohol (e.g. potassium t-pentoxide), followed by reaction successively with carbon disulphide and the alkyl halide. Both preparative procedures are illustrated in the following section. 

Ethers For the synthesis of ether, the Williamson ether synthesis is considered as the best method. It involves the SN2 reaction between a metal alkoxide and a primary alkyl halide or tosylate. The alkoxide needed for the reaction is obtained by treating an alcohol with a strong base like sodium hydride. An alternative procedure is to treat the alcohol directly with the alkyl halide in the presence of silver oxide, thus avoiding the need to prepare the alkoxide beforehand. 

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