6.2:
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 pKa 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.
6.2:
Nucleophilic Substitution Reactions
Historical perspective
In 1896, the German chemist Paul Walden discovered that he could interconvert pure enantiomeric (+) and (-) malic acids through a series of reactions. This conversion suggested the involvement of optical inversion during the substitution reaction. Further, in 1930, Sir Christopher Ingold described for the first time two different forms of nucleophilic substitution reactions, which are known as SN1 (nucleophilic substitution unimolecular) and SN2 (nucleophilic substitution bimolecular) reaction.
Nucleophilic substitution reaction
The word “substitution” is derived from the Latin word “substituō,” which means “to take the same place”. Nucleophilic substitution reactions are reactions in which a nucleophile, a Lewis base, reacts with an electrophile, a Lewis acid. The nucleophile substitutes the halogen atom bonded to the carbon of the molecule, releasing a stable ion called the leaving group. These reaction motifs are very similar to the Lewis acid/base reactions and involve very similar species:
• The electron-rich species analogous to the Lewis base is the nucleophile.
• The electron-deficient species analogous to the Lewis acid are electrophile.
General reaction:
Factors affecting the nucleophilic substitution reaction
Various factors govern the pathway of the nucleophilic substitution reaction:
- Nature of the substrate (primary, secondary, and tertiary alkyl halides)
- Strength of the nucleophile
- Strength of the electrophile
- Nature of the leaving group
- Temperature
- Solvent (protic vs. aprotic solvent)