S_N2 Reactions

Nucleophilic substitution reactions of alkyl halides take place by a continuum of mechanisms, defined by S_N2 behavior at one extreme and S_N1 behavior at the other. The essential characteristics of the S_N2 process include inversion of configuration at the reaction site, sensitivity to steric hindrance in the alkyl group, and second order kinetic behavior. The orbital interactions that take place in a successful S_N2 reaction are shown in the following diagram. The bonding and antibonding sigma molecular orbitals composing the C-X bond are drawn in the yellow box at the top of the diagram. As a nucleophile approaches the rear side of the carbon, the orbital containing the non-bonded electron pair (light blue) begins to overlap with the empty antibonding C-X sigma orbital (pink colored), shown on the left of the bottom line. As electrons occupy this antibonding orbital, the C-X bond is weakened. In the transition state partial bonds exists between the carbon and both the nucleophile and the halogen (the carbon is essentially sp² hybridized with the orange colored p-orbital providing the partial bonding). Finally, a full C-Nu sigma bond develops and the halogen leaves as an anion.  

Other substitution reactions also proceed by the S_N2 pathway, as illustrated by the stereoisomeric cyclohexyl tosylates in the following diagram. The bulky tert-butyl group on C-4 serves to lock the chair conformation in the configuration shown, so one isomer has an equatorial tosylate function, and the other an axial tosylate. On reaction with sodium thiophenolate, both isomers undergo bimolecular substitution with inversion, the axial isomer reacting about thirty times faster than its equatorial epimer. Steric hindrance to rear side nucleophile approach by the red colored hydrogen atoms is present for each isomer, but the relief of steric crowding of the axial tosylate leaving group helps to facilitate substitution of the that isomer.

S_N2 reactions may be intermolecular, as in these examples, or intramolecular. By clicking on the above equations, an example of two sequential substitutions, the first intermolecular and the second intramolecular, will be displayed. Note that the intramolecular substitution shown here proceeds via the same orbital alignment described above. The reacting moieties in intramolecular reactions are incorporated in the same molecule; consequently, such reactions exhibit first order kinetic behavior instead of the usual second order kinetics. Because enolate alkylation reactions are irreversible, the strained four-membered ring product is stable under the reaction conditions.
In general, intramolecular forms of bimolecular reactions are faster than their intermolecular counterparts, since the reactive sites are held close together (their relative concentrations are as high as possible). The rapid lactonization of gamma and delta-hydroxy acids compared with corresponding intermolecular esterifications is another example of this principle, which is associated with a favorable entropy change. Note, however, that ring size has a profound influence on the intra- vs. intermolecular dichotomy.

Maximum overlap of the electron orbital of the nucleophile with the antibonding sigma orbital of the carbon substituent requires an approach from the rear side of the carbon, ideally 180º from the leaving group. The importance of this orientation, which is shown in previous diagrams, was made clear by an experiment conducted by A. Eschenmoser over 25 years ago. The results of Eschenmoser's experiment are presented in the following illustration. Initially, two equations are written. The first describes the intermolecular methylation of a sulfone anion by methyl tosylate, a typical S_N2 reaction. The second is a very similar reaction which many would consider to be intramolecular, since a methyl sulfonate moiety is positioned ortho to the sulfone function.
By clicking on these equations, evidence against the intramolecular mechanism will be displayed. Although intramolecular reactions are often favored, this case requires a significant departure from the 180º orbital alignment required by an authentic S_N2 reaction. Since this reaction was found to be second order and is not faster than the simple intermolecular analog (reaction 1 on the preceding slide), it cannot be intramolecular.