The Substrate: Steric Effects in the SN2 Reaction

The first S_N2 reaction variable to look at is the structure of the substrate. Because the S_N2 transition state involves partial bond formation between the incoming nucleophile and the alkyl halide carbon atom, it seems reasonable that a hindered, bulky substrate should prevent easy approach of the nucleophile, making bond formation difficult. In other words, the transition state for reaction of a sterically hindered substrate, whose carbon atom is “shielded” from the approach of the incoming nucleophile, is higher in energy and forms more slowly than the corresponding transition state for a less hindered substrate (Figure 1.1).

Figure 1.1 Steric hindrance to the S_N2 reaction. As the models indicate, the carbon atom in (a) bromomethane is readily accessible, resulting in a fast S_N2 reaction. The carbon atoms in (b) bromoethane (primary), (c) 2 bromopropane (secondary), and (d) 2-bromo- 2-methylpropane (tertiary) are successively more hindered, resulting in successively slower S_N2 reactions.

As Figure 1.1 shows, the difficulty of nucleophile approach increases as the three substituents bonded to the halo-substituted carbon atom increase in size. Methyl halides are by far the most reactive substrates in S_N2 reactions, followed by primary alkyl halides such as ethyl and propyl. Alkyl branching at the reacting center, as in isopropyl halides (2°), slows the reaction greatly, and further branching, as in tert-butyl halides (3°), effectively halts the reaction.  Even branching one carbon away from the reacting center, as in 2,2-dimethylpropyl (neopentyl) halides, greatly hinders nucleophilic displacement.

As a result, S_N2 reactions occur only at relatively unhindered sites and are normally useful only with methyl halides, primary halides, and a few simple secondary halides. Relative reactivities for some different substrates are as follows:

Vinylic halides (R₂C= CRX) and aryl halides are not shown on this reactivity list because they are unreactive toward S_N2 displacement. This lack of reactivity is due to steric factors: the incoming nucleophile would have to approach in the plane of the carbon–carbon double bond and burrow through part of the molecule to carry out a backside displacement.