Stereospecificity of the bimolecular electrophilic substitution reaction

Question

We know that $\mathrm{S_N2}$ reactions always go with inversion at the saturated centre (they're stereospecific) and $\mathrm{E2}$ reactions are always anti (also stereospecific).

I recently observed in a paper an example of what was called an $\mathrm{S_E2}$ reaction, but can't understand how the stereochemistry could be predicted in this case? Is it also stereospecific, or is there some other factor involved?

Answer 1

The $\mathrm{S_E2}$ mechanism is most commonly found using organometallic reagents ($\ce{R-Li, R-MgBr}$ etc.) in which the metal is the electropositive element react with electrophiles.

Unlike with $\mathrm{S_N2}$, there are multiple stereochemical outcomes, which can make it difficult to determine whether the reaction is indeed stereospecific. This is described in Modern Physical Organic Chemistry (emphasis mine):

One of the most interesting aspects of these reactions is stereochemistry. Varying results are obtained depending upon the metal, the solvent, and the R-group.

_{Source: Modern Physical Organic Chemistry, Ansyln and Dougherty} ^[1]

Criterea for a stereospecific reaction

Before going any further, it may be instructive to define what we mean by stereospecific:

stereospecific is used for those reactions where the configuration of the starting material and the configuration of the product are related in a mechanistically constrained way

_{Source: Molecular Orbitals and Organic Chemical Reactions (Reference Edition), Fleming} ^[2]

What this means in practice is that if one enantiomer of a starting material gives one enantiomer of product, then the opposite enantiomer of starting material must give the opposite enantiomer of product. What stereospecific does not mean is high selectivity, many reactions are highly stereoselective but in no way mechanistically stereospecific (and equally stereospecific reactions are not always $100~\%$ stereoselective).

The empirical evidence

Unlike the $\mathrm{S_E2}$ reaction, where many examples have been studied, it has been considerably more challenging to examine the stereochemical cause of the $\mathrm{S_E2}$ reaction. In general, chiral alkyl-metal species are prone to racemisation (chiral Grignards, as an example, are barely known), and those chiral species that are stable and usually such for steric reasons (such as a constrained ring system).

Many of the experiments that have been conducted are described in March^[3], and the overwhelming majority of them go with retention (note that this doesn't necessarily imply a stereospecific process in itself and it has often been hard to study both enantiomers, for various reasons).

The orbital explanation

If we consider the orbitals involved during an $\mathrm{S_E2}$ reaction, it becomes clearer why there are multiple stereochemical outcomes, consider first $\mathrm{S_E2}$ at a saturated centre, such as $\ce{MeLi}$ attacking an electrophile :

_{Source: Molecular Orbitals and Organic Chemical Reactions (Reference Edition), Fleming} ^[2]

In this reaction, the electrophile is quite able to interact in such a way as to give rise to overall inversion or overall retention, in order to distinguish, these two electrophilic substitutions are labelled $\mathrm{S_E2}_\text{back}$ and $\mathrm{S_E2}_\text{front}$ respectively, though both are formally designated D_EA_E if the IUPAC system is followed.^[4]

This differs from the $\mathrm{S_N2}$ reaction in which inversion is almost always observed due to an anti-bonding interaction in the transition state if the nucleophile approaches in such a way as to give retention:

_{Source: Molecular Orbitals and Organic Chemical Reactions (Reference Edition), Fleming} ^[2]

Conclusion

The short answer is that it doesn't appear that the reaction is stereospecific. Orbitally speaking, there are two pathways leading to two different products (front or back attack), which may be observed in poor selectivity.

It appears, with the reactions studied so far, that the outcome is far more likely to be down to sterics/electronics as to whether the electrophile approaches from one side or the other

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References and Notes:

^{[1]: Ansyln, E.V.; Dougherty, D.A. Modern Physical Organic Chemistry; University Science Books:California, 2004}

^{[2]: I. Fleming Molecular Orbitals and Organic Chemical Reactions (Reference Edition); Wiley:Chichester, 2012}

^{[3]: March, J.; Smith, M.B. Advanced Organic Chemistry; Wiley:New Jersey, 2013}

^{[4]: IUPAC Recommendations for the Representation of Reaction Mechanisms: Acc. Chem. Res. 1989, 22, 343}