Anchimeric Assistance (Neighboring Group Participation)

The participation of neighboring groups in an S_N reaction is revealed by unique stereochemical results (retention in the substitution process) and also (usually) by obvious rate enhancements in comparison to a model in which neighboring group participation would be stereoelectronically impossible. Consider the case of trans-2-iodocyclohexyl brosylate (remember, brosylate is p-bromobenzenesulfonate, a very good leaving group, better even than tosylate (why?)).

In comparison to the corresponding cis isomer, the rate of solvolysis in acetic acetic is more than a million fold faster. This is because in the cis isomer, the iodo substituent cannot approach from the backside of the carbon which is undergoing substitution. Notice that a proper placement of leaving group and entering nucleophile in an S_N2 reaction requires a linear (or near-linear relationship between the C-leaving group bond and the C-nucleophile bond. This is feasible only when both the leaving group (here the brosylate) and the participating nucleophile (here the iodo substituent) are axial. This relationship is not available in the more stable diequatorial conformer of the trans isomer, but can be achieved readily by a ring flip to form the somewhat less stable diaxial conformer. However, in the cis isomer, neither conformation available has the appropriate diaxial relationship. The reaction therefore proceeds without neighboring group participation, and as expected, via an S_N1 reaction, which gives a mixture of cis and trans product acetates. Incidentally, why would an S_N1 mechanism be favored over an S_N2 mechanism for this brosylate?

Iodo substituents are powerful neighboring groups, but many other groups having unshared electron pairs can do the same thing. Bromine produces a rate enhancement of amost 10³, while chlorine gives a much smaller rate enhancement, along with analogous stereochemical results. Incidentally, an acetate substituent is also a powerful neighboring group (rate enhancement ca. 10³). Benzamido is extremely powerful as a leaving group.