Nucleophilic Substitution Reactions

Many organic chemistry reactions proceed under acid or base-catalyzed conditions, including nucleophilic substitution reactions.

Consider a simple acid-base reaction of hydrochloric acid with sodium hydroxide. Here, the hydroxide ion is an electron-rich species and acts as a Lewis base. It deprotonates the acidic hydrogen, forming water and chloride ions as the conjugate base of HCl.

Now, consider a nucleophilic substitution reaction between chloromethane and sodium hydroxide. Sodium hydroxide remains the electron-rich component referred to as a nucleophile. The hydroxide ion is the conjugate base of water, which is a weak acid with a pK_a of 15.7. Thus, it is a strong conjugate base and a strong nucleophile.

Chloromethane, on the other hand, is a primary alkyl halide. Here the electron-deficient component is analogous to a Lewis acid and is called an electrophile.

Similar to an acid-base reaction, the hydroxide ion reacts with the electrophile by donating its lone pair of electrons and forming a new bond with the carbon.

Simultaneously, the bond between the chloride, called the leaving group, and the carbon breaks, and the chloride ion leaves, taking both electrons with it.

However, a nucleophilic substitution can proceed in a different way too. Consider the reaction between 2-bromo-2-methylpropane, a tertiary substrate, and water, where it functions as a solvent as well as a nucleophile. A reaction where a solvent behaves as a nucleophile is known as solvolysis.

Upon ionization in the polar solvent, the bond between the tertiary substrate and the leaving group breaks first. The leaving group takes both electrons from the bond, forming a stabilized carbocation.

Water, having two lone pairs, acts as the nucleophile and donates one electron pair to the electrophilic carbocation forming an oxonium species. Following deprotonation, 2-methylpropan-2-ol is formed.

But what dictates the reaction mechanism? As shown in later lessons, the mechanism of a nucleophilic substitution is influenced by the nature of the substrate, leaving group, nucleophile, electrophile, and solvent polarity.