Halides, alkyl, preparation from alcohols

PREPARATION OF ALKYL HALIDES 1. From alcohols. Discussed in Secs. 16.4-16.5. 

We now have a new problem Where does the necessary alkene come from Alkenes are prepared from alcohols by acid catalyzed dehydration (Section 5 9) or from alkyl halides by dehydrohalogenation (Section 5 14) Because our designated starting material is tert butyl alcohol we can combine its dehydration with bromohydrm formation to give the correct sequence of steps... 

Section 8 14 Nucleophilic substitution can occur with leaving groups other than halide Alkyl p toluenesulfonates (tosylates) which are prepared from alcohols by reaction with p toulenesulfonyl chloride are often used... 

A reaction useful only with sub strates that do not undergo E2 elimi nation readily It is rarely used for the synthesis of alcohols since alkyl halides are normally prepared from alcohols... 

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)... 

Sulfonate esters are especially useful substrates in nucleophilic substitution reactions used in synthesis. They have a high level of reactivity, and, unlike alkyl halides, they can be prepared from alcohols by reactions that do not directly involve bonds to the carbon atom imdeigoing substitution. The latter aspect is particularly important in cases in which the stereochemical and structural integrity of the reactant must be maintained. Sulfonate esters are usually prepared by reaction of an alcohol with a sulfonyl halide in the presence of pyridine ... 

An advantage that sulfonate esters have over alkyl halides is that their preparation from alcohols does not involve any of the bonds to carbon. The alcohol oxygen becomes the oxygen that connects the alkyl group to the sulfonyl group. Thus, the configuration of a sulfonate ester is exactly the same as that of the alcohol from which it was prepared. If we wish to study the stereochemistry of nucleophilic substitution in an optically active substrate, for example, we know that a tosylate ester will have the same configuration and the same optical purity as the alcohol from which it was prepared. 

Both the alkyl halide and the alkoxide ion are prepared from alcohols. The problem then becomes one of preparing the appropriate alcohol (or alcohols) from the starting ester. This is readily done using lithium aluminum hydride. 

Sulfonates such as mesylates or tosylates are readily prepared from alcohols under mild conditions, and are therefore attractive alternatives to halides as electrophiles. Although sulfonates often undergo clean displacement by nucleophiles, alternative reaction pathways are accessible to these intermediates, which can lead to unexpected results. If the nucleophile used is strongly basic, metalation instead of displacement of the sulfonate can occur. Some potential reactions of such metalated sulfonates include fragmentation into sulfenes and alcoholates, or into sulfmates and carbonyl compounds, or self-alkylation (Scheme4.15). 

Alcohols and phenols are also weak bases. They can be protonated on the oxygen by strong acids. This reaction is the first step in the acid-catalyzed dehydration of alcohols to alkenes and in the conversion of alcohols to alkyl halides by reaction with hydrogen halides. Alkyl halides can also be prepared from alcohols to alkyl halides by reaction with hydrogen halides. Alkyl halides can also be prepared from alcohols by reaction with thionyl chloride or phosphorus halides. 

Alkyl halides may be prepared from alcohols by substitution reactions and from alkenes by addition reactions. 

Williamson s S3mthesis.—This reaction is known as Williamson s synthesis because, in 1851, he showed, by it, the true constitution of ether, and made possible the explanation of its preparation from alcohol and sulphuric acid as given a little later on. The reaction is similar to the Wurtz reaction between sodium and an alkyl halide by which a hydrocarbon is formed. 

Reduction of an alkyl halide, either via the Grignard reagent or directly with metal and acid, involves simply the replacement of a halogen atom by a hydrogen atom the carbon skeleton remains intact. This method has about the same applicability as the previous method, since, like alkenes, alkyl halides are generally prepared from alcohols. Where either method could be used, the hydrogenation of alkenes would probably be preferred because of its simplicity and higher yield. 

As we shall see later, alkyl halides are generally prepared from the corresponding alcohols, and hence both these methods ultimately involve preparation from alcohols howevei, dehydrohalogenation generally leads to fewer complications and is often the preferred method despite the extra step in the sequence. ... 

Alkyl halides are nearly always prepared from alcohols which are available commercially (Sec. 15.5) or are readily synthesized (Secs. 15.7 and 16.9-16.10). Although certain alcohols tend to undergo rearrangement (Sec. 16.4) during replacement of —OH by —X, this tendency can be minimized by use of phosphorus halides. 

Like alkyl halides, alkyl sulfonates are prepared from alcohols but, as we shall see in Sec. 16.7, the two syntheses differ in one very important way. 

By far the most important method of preparing alcohols is the Grignard synthesis. This is an example of the second approach, since it leads to the formation of carbon-carbon bonds. In the laboratory a chemist is chiefly concerned with preparing the more complicated alcohols that he cannot buy these are prepared by the Grignard synthesis from rather simple starting materials. The alkyl halides from which the Grignard reagents are made, as well as the aldehydes and ketones themselves, are most conveniently prepared from alcohols thus the method ultimately involves the synthesis of alcohols from less complicated alcohols. 

Hydrolysis of alkyl halides is severely limited as a method of synthesizing alcohols, since alcohols are usually more available than the corresponding halides indeed, the best general preparation of halides is from alcohols. The synthesis of benzyl alcohol from toluene, however, is an example of a useful application of this method. 

Let us try to get a broader picture of the synthesis of complicated alcohols. We learned (Sec. 15.12) that they are most often prepared by the reaction of Grignard reagents with aldehydes or ketones. In this chapter we Have learned that aldehydes and ketones, as well as the alkyl halides from which the Grignard reagents are made, are themselves most often prepared from alcohols. Finally, we know that the simple alcohols are among our most readily available compounds. We have available to us, then, a synthetic route leading from simple alcohols to more complicated ones. 

Alkyl halides are prepared from alcohols by use of hydrogen halides or phosphorus halides. Phosphorus halides are often preferred because they tend less to bring about rearrangement (Sec. 16.4). 

Alkenes are prepared from alcohols either by direct dehydration or by de-hydrohalogenation of intermediate alkyl halides to avoid rearrangement we often select dehydrohalogenation of halides even though this route involves an extra step. (Or, sometimes better, we use elimination from alkyl sulfonates.)... 

Alcohols react with HX to form alkyl halides, but the reaction works well only for tertiary alcohols, R,COH. Primaiy and secondary alkyl halides are normally prepared from alcohols using either SOClj or PBr ). Alkyl halides react with magnesium in ether solution to form organomagnesium halides, or Grignard ret ents (RM O- Since Grignard reagents are both nucleophilic and basic, they react with acids to yield hydrocarbons. The overall result of Grignard formation and protonation is the conversion of an alkyl halide into an alkane (RX— RM RH). 

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