Frontside vs. Backside Attacks

A biomolecular nucleophilic substitution (S_N2) reaction is a type of nucleophilic substitution whereby a lone pair of electrons on a nucleophile attacks an electron deficient electrophilic center and bonds to it, resulting in the expulsion of a leaving group. It is possible for the nucleophile to attack the electrophilic center in two ways.

• Frontside Attack: In a frontside attack, the nucleophile attacks the electrophilic center on the same side as the leaving group. When a frontside attack occurs, the stereochemistry of the product remains the same; that is, we have retention of configuration.
• Backside Attack: In a backside attack, the nucleophile attacks the electrophilic center on the side that is opposite to the leaving group. When a backside attack occurs, the stereochemistry of the product does not stay the same. There is inversion of configuration.

The following diagram illustrates these two types of nucleophilic attacks, where the frontside attack results in retention of configuration; that is, the product has the same configuration as the substrate. The backside attack results in inversion of configuration, where the product's configuration is opposite that of the substrate.

Experimental Observation: All S_N2 Reactions Proceed With Nucleophilic Backside Attacks

Experimental observation shows that all S_N2 reactions proceed with inversion of configuration; that is, the nucleophile will always attack from the backside in all S_N2 reactions. To think about why this might be true, remember that the nucleophile has a lone pair of electrons to be shared with the electrophilic center, and the leaving group is going to take a lone pair of electrons with it upon leaving. Because like charges repel each other, the nucleophile will always proceed by a backside displacement mechanism.