Neopentyl halides, nucleophilic substitution

Dimethylpropyl group Neopentyl halides, nucleophilic substitution... 

The alkyl halides that react by the S l mechanism have a relatively low reactivity toward polar nucleophilic substitution due to steric, electronic or strain factors11, as shown for several bicycloalkyl, cycloalkyl and neopentyl halides and for /-butyl chloride. In the following section the reaction of these alkyl halides with different nucleophiles will be discussed. 

Neopentyl halides are among the most unreactive substrates in polar nucleophilic substitution reactions118. Due to the fact that the halogens are on a primary carbon atom, neopentyl halides seldom react by the S l mechanism. Beacuse of the steric hindrance by the t-butyl group to backside attack, the S 2 reaction in the neopentyl system is notoriously slow. However, with nucleophiles that are good electron donors, the ET reaction competes with the polar mechanism. 

ProUem 146 Neopentyl halides are notoriously slow in nucleophilic substitution, whatever the experimental conditions. How can you account for this ... 

Successful substitutions at neopentyl-type substrates can be performed, but can be accompanied by rearrangements. The best results are obtained with small nucleophiles, for example halides, azide, or cyanide. Some representative examples are shown in Scheme 4.20, to illustrate the reaction conditions required. If electron-rich nucleophiles such as thiolates are used, substitutions at neopentyl derivatives can also occur via SET [95],... 

Not only radical scavengers, radical reduction and/or radical dimerization products but also radical probes were used in order to prove the presence of radicals as intermediates along the S l propagation cycle. Thus the formation of cyclized and uncyclized substitution products was taken as an indication of radical intermediates in the reaction of neopentyl-type halides containing a cyclizable probe of the 5-hexenyl type 2. These reactions were performed with PhS and Ph2P ions as nucleophiles (equation 13)52. 

Another interesting use of TEMPO has been in free-radical substitution of alkyl halides. In this reaction, halides react with tributyltin hydride and TEMPO to yield A-alkoxyamine substitution products [18. This reaction is especially attractive in cases where anionic nucleophiles are sterically prevented from carrying out substitution reactions. An example of this can be seen in Barrett s synthesis of sucrose [18b], in which a stereoselective iodoetherification reaction was used to produce neopentyl alkyl iodide 13 (Scheme 5). Free radical substitution mediated by tributyltin hydride and TEMPO yielded A-alkoxyamine 14. The mechanism [19] involves TEMPO abstraction of hydrogen from tributyltin hydride [20] the stannyl radical then abstracts iodide from the substrate, and a second equivalent of TEMPO traps the resulting carbon radical. 

The second-order rate constants for the substitution reactions of alkyl halides generally decrease as the aUcyl halide varies from methyl to 1° to 2° to 3°. This trend is illustrated in Table 8.9, which summarizes kinetic data for alkyl bromides (R-Br) reacting with bromide ion. ° This trend is usually ascribed to increasing steric hindrance to back-side attack of the nucleophile as hydrogens bonded to the C—Br carbon atom are replaced with larger alkyl groups. Theoretical calculations and gas phase studies have provided support for this explanation. It is notable that neopentyl bromide is less reactive than... 

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