Alkoxide ions with alkyl halides

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

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. 

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... 

Formation of an ether by the SN2 reaction of an alkoxide ion with an alkyl halide or tosylate. In general, the electrophile (R —X) must be primary, or occasionally secondary, (p. 635)... 

The reactivity of 02 - with alkyl halides in aprotic solvents occurs via nucleophilic substitution. Kinetic studies confirm that the reaction order is primary > secondary > tertiary and I > Br > Cl > F for alkyl hahdes, and that the attack by 02 - results in inversion of configuration (Sn2). Superoxide ion also reacts with CCI4, Br(CH2)2Br, CeCle, and esters in aprotic media. The reactions are via nucleophilic attack by 02 on carbon, or on chlorine with a concerted reductive displacement of chloride ion or alkoxide ion. As with all oxyanions, water suppresses the nucleophilicity of 02 (hydration energy, lOOkcalmoL ) and promotes its rapid hydrolysis and disproportionation. The reaction pathways for these compounds produce peroxy radical and peroxide ion intermediates (ROO and ROO ). 

Ethers are compounds that have two organic groups bonded to the same oxygen atom, ROR. The organic groups can be alkyl, vinylic, or aryl, and the oxygen atom can be in a ring or in an open chain. Ethers are prepared by either the Williamson ether synthesis, which involves Sf t2 reaction of an alkoxide ion with a primary alkyl halide, or the alkoxymercuration reaction, which involves Markovnikov addition of an alcohol to an alkene. 

Thiols are sulfur analogs of alcohols. They are stronger acids and have lower boiling points than alcohols. Thiolate ions are weaker bases and better nucleophiles in protic solvents than alkoxide ions. Sulfur analogs of ethers are called sulfides or thioethers. Sulfides react with alkyl halides to form sulfonium salts. 

Arsenic and Antimony. Three studies of reaction mechanisms for tetrahedral antimony(v) compounds are reported. These are of the reaction of trimethylantimony sulphide (MegSbS) with alkyl halides, where a four-centre transition state seems possible, the reaction of R4Sb+ cations with alkoxide ions, and the ageing of antimonic acid in aqueous solution. Both thermal and photochemical decomposition of pentaphenylanti-mony have been investigated. Whereas the products of the photochemical reaction are numerous, though all derived from phenyl radicals, the... 

In Chapter 15, Grignard reagents react as bases, but they are poor nucleophiles with alkyl halides. Grignard reagents are good nucleophiles with ketones or aldehydes, however, and these reactions will be discussed in more detail in Chapter 18. For the moment, the point of this example is to see that nucleophiles react with ketones and aldehydes by acyl addition. In each example, the alkoxide products 30-32 are converted to an alcohol via an acid-base reaction where the alkoxide is the base and aqueous acid (H+) is used. The alcohol product is the conjugate acid of this reaction and, because the hydronium ion is used as an acid, water is the conjugate base in this second reaction. This second chemical reaction is necessary in order to isolate a neutral product. 

Williamson ether synthesis reaction of an alkoxide ion with an alkyl halide (10.10). 

Alkanethiolate ions (RS ) are weaker bases than alkoxide ions (RO ) and undergo synthetically useful 8 2 reactions even with secondary alkyl halides... 

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 be prepared by reaction of an alkoxide or phenoxide ion with a primary alkyl halide. Anisole, for instance, results from reaction of sodium phenoxide with iodomethane. What kind of reaction is occurring Show the mechanism. 

Another method for the synthesis of epoxides is through the use of halo-hydrins, prepared by electrophilic addition of HO—X to alkenes (Section 7.3). When halohydrins are treated with base, HX is eliminated and an epoxide is produced by an intramolecular Williamson ether synthesis. That is, the nucleophilic alkoxide ion and the electrophilic alkyl halide are in the same molecule. 

Williamson ether synthesis (Section 18.2) A method for synthesizing ethers by S 2 reaction of an alkyl halide with an alkoxide ion. 

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. 

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. 

Elimination reactions can also occur when a carbon halogen bond does not completely ionize, but merely becomes polarized. As with the El reactions, E2 mechanisms occur when the attacking group displays its basic characteristics rather than its nucleophilic property. The activated complex for this mechanism contains both the alkyl halide and the alkoxide ion. 

This method cannot be used with tertiary alkyl halides, because the competing elimination reaction predominates. The elimination reaction occurs because the rearward approach that is needed for an S 2 mechanism is impossible due to steric hindrance. An S 1 mechanism is likewise unfavored, because as the 3° carbon attempts to become a carbocation, the hydrogens on the adjacent carbons become acidic. Under these conditions, the alkoxide ion begins to show less nucleophilic character and, correspondingly, more basic character. This basic character leads to an acid-base reaction, which results in the generation of an elimination product (an alkene). 

When the halide is bonded to an allylic system (CH CH-CH -X) an alkoxide ion will react analogously to the previously described S 2 displacement on an alkyl halide. The most significant difference is the rate enhancing effect of the alkene moiety which has been attributed to a decrease in the activation energy of the reaction (9). A second possible mode of reaction is available with allylic halides. This mode of displacement is usually called S 2 and, in general, will be promoted relative to the normal displacement when there are substituents on the alpha carbon which tend to inhibit the normal SN2 pathway by inductive or steric effects (Reaction VII). 

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