Neighbouring group assistance

We have seen that photolytic halogenation usually leads to a wide variety of products with little or no selectivity. However, the bromination of alkyl bromides gives about 90 per cent substitution on the adjacent carbon. Furthermore, if the adjacent carbon is chiral then it retains its configuration. Suggest a mechanism that may account for these experimental observations. 

By invoking the assistance of the neighbouring bromine and forming a cyclic free radical intermediate, the retention of configuration and the selectivity of substitution is explained. 

This cyclic free radical has obvious similarities to the involvement of a neighbouring group in SN2 reactions. In those situations, the rate of the reaction was often increased, because of the favourable entropic factor. Normally in 

The /-butyl group must always be in the equatorial position, and so this determines the position of the smaller bromo substituent. In the cis isomer, the bromo substituent is in the axial position and so is capable of acting as a neighbouring species in the radical substitution reaction. This promotes substitution on the adjacent carbon, and also increases the rate of reaction. In the tram isomer, the bromine is in the equatorial position, and so cannot assist the substitution reaction in this way. 

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The dehalogenation of the a-haloalkyl radical is a fast step which can take place by several possible routes . Dibromides are reduced much faster than dichlorides and rra j-l,2-dibromocylohexane is reduced 100 times faster than the m-isomer. This accords with neighbouring group assistance which bromine seems particularly capable of offering (see subsection 6.4.10). 

Scheme 24 Neighbouring group assistance of sulfide oxidation.

Chandrasekhar S, Mohapatra S (1998) Neighbouring Group Assisted Sulfonamide Cleavage of Sharpless Aminols under Acetonation Conditions. Tetrahedron Lett 39 695... 

C for periods of up to 6h. In other cases, amides have resisted hydrolysis even during reflux in 48% hydrobromic acid/acetic acid (2). Helmchen el al. [63] reported the directed separation and recovery of acids by neighbouring group assisted hydrolysis. Using amino alcohols as chiral reagents to form amides with the hydroxyl function y or to the carbonyl gave excellent separation factors, and also allowed the hydrolysis to be carried out under somewhat milder conditions, e.g. in 3 M sulphuric acid. 

The substituted indanone (20) has been found to give (21) stereospecifically, and the exo-vinylcyclopropane (23) has been obtained in good yield by neighbouring-group-assisted cyclization of (22). Reductive cyclizations of a -unsaturated ketones... 

Neighbouring group participation is occasionally called anchlmeric assistance (Greek anchi = neighbouring merpart). 

You ve already met the most important ones—sulfides, esters, carboxylates. Ethers and amines (you will see some of these shortly) can also assist substitution reactions through neighbouring group participation. The important thing that they have in common is an electron-rich heteroatom with a lone pair that can be used to form the cyclic intermediate. Sulfides are rather better than ethers—this sulfide reacts with water much faster than rc-PrCl but the ether reacts with acetic acid four times more slowly than rc-PrOSC Ar. 

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