Halides, alkyl, reaction with azide

As expected, substitution by azide ion occurs more readily when the alkyl substrate bears electron-withdrawing groups. For example phenacyl bromide and its derivatives give high yields of azides when treated with sodium azide in the cold °. Secondary alkyl substrates undergo Sj,2 reactions with azide ion ° ° but with less facility than primary alkyl substrates in accordance with the normal polar influences and primary steric eflfects in reactions . Selective substitution is therefore possible and this has been effectively applied in carbohydrate and steroid synthesis (sections II.B.5,6). These effects are also exemplified in the alicyclic series where it has been reported that menthyl halides and 2-methylcyclohexyl halides afford unsatisfactory yields of azide ° . The unsubstituted alicyclic azides, however, are obtained in good yields by the procedures outlined above(Table 1). 

The acceleration of substitution reactions with azides using ultrasound techniques (Scheme 31) has not yet been investigated in detail. Activated primary halides react with trimethylsilyl azide (TMS-A) under particularly mild and absolutely neutral conditions (Scheme 31). Secondary and tertiary cyclic halides were treated with TMS-A/SnCU in CH2CI2 or CHCI3 to yield the corresponding azido compounds." Very impressive results with yields of about 90% were in this case reported in the adamantane and diamantane series." High solubility in organic solvents is also noticed with acetyl azide, which, prepared in situ, has also been used for azide syntheses. The scope of this reaction has still to be determined, however." Hassner noticed nearly quantitative yields of azides when alkyl halides (or tosyl-ates) were treated with polymeric quaternary ammonium azides. 

A better method for preparing primary amines is to use the azide synthesis, in which azjde ion, N3, is used for SN2 reaction with a primary or secondary alkyl halide to give an alkyl azide, RN3. Because alkyl azides are not nucleophilic, overalkylation can t occur. Subsequent reduction of the alkyl azide, either by catalytic hydrogenation over a palladium catalyst or by reaction with LiAlK4. then leads to the desired primary amine. Although the method works well, low-molecular-weight alkyl azides are explosive and must be handled carefully. 

Azide synthesis (Section 24.6) A method for preparing amines by S 2 reaction of an alkyl halide with azide ion, followed by reduction. 

Tertiary alkyl azides can be prepared by stirring tertiary alkyl chlorides with NaN3 and ZnCl2 in 82 ° or by treating tertiary alcohols with NaN3 and CF3-COOH or with HN3 andTiCl4 or BF3. Acyl azides, which can be used in the Curtius reaction (18-14), can be similarly prepared from acyl halides, anhydrides, " esters, or other acyl derivatives. ° Acyl azides can also be prepared... 

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. 

A one-pot PTC reaction procedure for the overall conversion of an alkyl halide into a primary amine via an azide is particularly illustrative.204 Thus the reduction of the azide is effected by the addition of sodium borohydride to a reaction mixture arising from the PTC displacement reaction of an alkyl halide with sodium azide (the preparation of 1-octylamine, Expt 5.193). The reaction appears to be applicable to primary and secondary alkyl halides, alkyl methane-sulphonates and benzylic halides. 

Reaction of alkyl halides with dimethvl hydrazine184 and by initial formation of azides followed by reaction with borohydride185 also gives routes for their interconversion into amines. 

Ingold s (1957) calculations are for differences in an intrinsic entropy and enthalpy difference between a series of alkyl halides and their transition states. Two important requirements of his calculations are that differences in activation energy and in entropy of activation, for any one set of Finkelstein reactions, be independent of solvent and of salt effects as the alkyl group is changed. These requirements are tested in Table 25 and in Figs. 5, 6, and 7, for one Finkelstein reaction, of alkyl bromides with chloride ion, and for a closely related reaction, that of azide ion with alkyl bromides. 

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