Halides, alkyl reaction with halide ions

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. 

The reaction often works poorly unless an excess of the nucleophile is used because the product thiol can undergo a second S 2 reaction with alkyl halide to give a sulfide as a by-product. To circumvent this problem, thiourea, (NH2J2C=S, is often used as the nucleophile in the preparation of a thiol from an alkyl halide. The reaction occurs by displacement of the halide ion to yield an intermediate alkyl isothiourea salt, which is hydrolyzed by subsequent reaction with aqueous base. 

It is these reactions that are thought to provide some justification for equation (vii) [in Section VI B3] according to which p-phenethylbi-guanide in methanol exists to some extent as biguanidium methoxide. This being so, the reaction with alkyl halides is the nucleophihc displacement of the halogen ion by methoxide with formation of the methyl ether and the salt of the biguanide. 

The Friedel-Crafts reaction with alkyl halides (p. 260) or acid chlorides (p. 260) is a well-known example of a reaction which proceeds through carbonium ions formed by this mechanism. 

Trialkyl phosphites undergo the Michaelis-Arbusov reaction with alkyl halides to give dialkyl phosphonates the initial phosphonium ion is attacked at one the alkyl groups by the newly liberated halide. The reaction is useful in producing non-fissile but isosteric analogues of activated sugars for mechanistic studies (Figure 6.51). ... 

Phosphorothioate ions are also 0,S-ambident. Their reactions with alkyl halides and sulfenyl chlorides occur at the sulfur (25). 

Alkylation of aromatic compounds (eqs. 4.10 and 4.11) is referred to as the Friedel-Crafts reaction, after Charles Friedel (French) and James Mason Crafts (American), who first discovered the reaction in 1877. The electrophile is a carbocation, which can be formed either by removing a halide ion from an alkyl halide with a Lewis acid catalyst (for example, AICI3) or by adding a proton to an alkene. For example, the synthesis of ethylbenzene can be carried out as follows ... 

Nitriles are common nitrogen-containing compounds. In Chapter 11 (Section 11.3.6), cyanide ion reacted as a nucleophile in an Sn2 reaction with alkyl halides to give a nitrile. When 2-bromohexane (22) is treated with NaCN in DMF, the product is 2-cyanohexane, 23. Reduction of this nitrile with LiAlH4 gives a primary amine, in this case l-amino-2-methylhexane 24. 

The first reaction is a nucleophilic substitution reaction. Triphenylphosphine is an excellent nucleophile and a weak base. It reacts readily with 1° and 2° aUcyl halides by an Sn2 mechanism to displace a halide ion from the alkyl halide to give an alkyltriphenylphosphonium salt. The second reaction is an acid-base reaction. A strong base (usually an alkyllithium or phenyllithium) removes a proton from the carbon that is attached to phosphorus to give the ylide. 

Na will bind in the cavity of [15]-crown-5 and the inclusion compound will be soluble in the nonpolar solvent because the outside of the crown is composed primarily of nonpolar C—H bonds. The inclusion compound must carry a counterion to balance its positive charge. Thus, cyanide ion will also be in the nonpolar solvent, where it will be a powerful nucleophile since it will not be solvated. In this way, nucleophilic substitution reactions with alkyl halides that are soluble only in nonpolar solvents can readily take place. 

We saw in Chapter 9 that an alcohol can be obtained by substituting a halide ion in an alkyl halide with hydroxide ion. However, in Chapter 10, we found that a competing elimination reaction diminishes the yield in the substitution reaction because the nucleophilic hydroxide ion is also a strong base. In Section 15.7, we will examine an alternative substitution reaction that takes into account this potential competing reaction. 

The Williamson ether synthesis is the most widely used method to produce ethers. It occurs by an Sj 2 reaction in which a metal alkoxide displaces a halide ion from an alkyl halide. The aUcoxide ion is prepared by the reaction of an alcohol with a strong base such as sodium hydride. 

The properties of organometallic compounds are much different from those of the other classes we have studied to this point Most important many organometallic com pounds are powerful sources of nucleophilic carbon something that makes them espe cially valuable to the synthetic organic chemist For example the preparation of alkynes by the reaction of sodium acetylide with alkyl halides (Section 9 6) depends on the presence of a negatively charged nucleophilic carbon m acetylide ion... 

Nucleophilic substitution by azide ion on an alkyl halide (Sections 8 1 8 13) Azide ion IS a very good nucleophile and reacts with primary and secondary alkyl halides to give alkyl azides Phase transfer cata lysts accelerate the rate of reaction... 

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