What is a Nucleophilic Addition Reaction?
A nucleophilic addition reaction is a chemical addition reaction in which a nucleophile forms a sigma bond with an electron deficient species. These reactions are considered very important in organic chemistry since they enable the conversion of carbonyl groups into a variety of functional groups. Generally, nucleophilic addition reactions of carbonyl compounds can be broken down into the following three steps.
- The electrophilic carbonyl carbon forms a sigma bond with the nucleophile.
- The carbon-oxygen pi bond is now broken, forming an alkoxide intermediate (the bond pair of electrons are transferred to the oxygen atom).
- The subsequent protonation of the alkoxide yields the alcohol derivative.
The carbon-oxygen double bond is directly attacked by strong nucleophiles to give rise to the alkoxide. However, when weak nucleophiles are used, the carbonyl group must be activated with the help of an acid catalyst for the nucleophilic addition reaction to proceed.
The carbonyl group has a coplanar structure and its carbon is sp2 hybridized. However, the attack of the nucleophile on the C=O group results in the breakage of the pi bond. The carbonyl carbon is now sp3 hybridized and forms a sigma bond with the nucleophile. The resulting alkoxide intermediate has a tetrahedral geometry, as illustrated above.
Why do Carbonyl Compounds Undergo Nucleophilic Addition?
In carbonyl compounds, the carbon-oxygen bond is polar. Owing to the relatively higher electronegativity of the oxygen atom, the electron density is higher near the oxygen atom. This leads to the generation of a partial negative charge on the oxygen atom and a partial positive charge on the carbon atom.
Since the carbonyl carbon holds a partial positive charge, it behaves as an electrophile. The partial negative charge on the oxygen atom can be stabilized via the introduction of an acidic group. The proton donated by the acid bonds with the carbonyl oxygen atom and neutralizes the negative charge.
Aldehydes are relatively more reactive towards nucleophilic addition reactions when compared to ketones. This is because the secondary carbocations formed by ketones are stabilized by the adjacent R groups. The primary carbocations formed by aldehydes are less stable than the secondary carbocations formed by ketones and are, therefore, more susceptible to nucleophilic attacks.
Reactions with Hydrogen Cyanide
The nucleophilic addition reaction between hydrogen cyanide (HCN) and carbonyl compounds (generally aldehydes and ketones) results in the formation of cyanohydrins. Base catalysts are often used to increase the rate of the reaction. The cyanide anion (CN–) acts as a powerful nucleophile and attacks the carbonyl carbon to form a new sigma bond, as illustrated below.
The polar nature of the C=O bond makes the carbonyl carbon electrophilic in nature. The cyanide anion executes a nucleophilic attack on the carbonyl carbon, resulting in the formation of an intermediate. This intermediate is now protonated to afford the cyanohydrin product.
Nucleophilic Additions with Monohydric Alcohols
Aldehydes and ketones undergo nucleophilic addition reactions with monohydric alcohols to yield hemiacetals. Upon further reaction with another molecule of the alcohol, an acetal is obtained. Since alcohols are weak nucleophiles, the reaction requires an acid catalyst for the activation of the carbonyl group towards nucleophilic attack.
Since the hemiacetals can undergo hydrolysis to yield the reactants (the alcohol and carbonyl compound), the water formed during the reaction must be removed. In this reaction, the carbonyl oxygen is protonated before the nucleophilic attack is carried out by the alcohol. The nucleophilic alcohol is now deprotonated to form the hemiacetal. This reaction can be repeated to obtain the acetal.
Nucleophilic Addition with Grignard Reagents
The polar nature of Grignard reagents (general formula: R-Mg-X) attributes a partial negative charge to the carbon atom. The following types of alcohols are formed from nucleophilic addition reactions with Grignard reagents.
- Primary alcohols are formed when formaldehyde is used.
- Other aldehydes yield secondary alcohols upon reacting with Grignard reagents.
- The nucleophilic addition reactions between ketones and Grignard reagents yield tertiary alcohols.
The general mechanism of these reactions involves the attack of the nucleophilic carbon (belonging to R-Mg-X) on the carbonyl carbon. A simple acid workup of the resulting alkoxide yields the corresponding alcohol.
Reaction with Primary Amines
The reaction between primary amines and aldehydes/ketones yields imine derivatives along with water. The reaction can be illustrated as follows.
Initially, the nucleophilic nitrogen belonging to the amine attacks the carbonyl carbon. The carbon-oxygen double bond is broken and a new carbon-nitrogen sigma bond is formed. Now a proton is transferred from the amine to the oxygen atom. In the next step of this nucleophilic addition reaction, The OH group is further protonated and water is removed. The carbon atom now forms a double bond with the nitrogen belonging to the amine. This nitrogen is now deprotonated to afford the required imine product.