The S_N2 mechanism

There are two mechanistic models for how an alkyl halide can undergo nucleophilic substitution. In the first picture, the reaction takes place in a single step, and bond-forming and bond-breaking occur simultaneously. (In all figures in this section, 'X' indicates a halogen substituent).

This is called an 'S_N2' mechanism. In the term S_N2, S stands for 'substitution', the subscript N stands for 'nucleophilic', and the number 2 refers to the fact that this is a bimolecular reaction: the overall rate depends on a step in which two separate molecules (the nucleophile and the electrophile) collide. A potential energy diagram for this reaction shows the transition state (TS) as the highest point on the pathway from reactants to products.

If you look carefully at the progress of the S_N2 reaction, you will realize something very important about the outcome. The nucleophile, being an electron-rich species, must attack the electrophilic carbon from the back side relative to the location of the leaving group. Approach from the front side simply doesn't work: the leaving group - which is also an electron-rich group - blocks the way.

The result of this backside attack is that the stereochemical configuration at the central carbon inverts as the reaction proceeds. In a sense, the molecule is turned inside out. At the transition state, the electrophilic carbon and the three 'R' substituents all lie on the same plane.

What this means is that S_N2 reactions whether enzyme catalyzed or not, are inherently stereoselective: when the substitution takes place at a stereocenter, we can confidently predict the stereochemical configuration of the product. Below is an animation illustrating the principles we have just learned, showing the S_N2 reaction between hydroxide ion and methyl iodide. Notice how backside attack by the hydroxide nucleophile results in inversion at the tetrahedral carbon electrophile.

We will be contrasting about two types of nucleophilic substitution reactions. One type is referred to as unimolecular nucleophilic substitution (S_N1), whereby the rate determining step is unimolecular and bimolecular nucleophilic substitution (S_N2), whereby the rate determining step is bimolecular. We will begin our discussion with S_N2 reactions, and discuss S_N1 reactions elsewhere.