Nucleophilic Addition Reaction

A nucleophilic addition reaction occurs when a nucleophile (electron-rich species) adds to a molecule containing a carbon-oxygen double bond (C=O). These reactions are common in aldehydes and ketones. Considering the steric and electronic factors (inductive effect) of the group attached to the carbonyl carbon, the reactivity of the carbonyl groups decreases in the order:
H₂C = O > RCHO > R₂CO > ArCHO > Ar₂CO.

Polar functional groups, e.g., >C=O, –C≡N, >C=S, etc., also undergo nucleophilic addition. The hetero atoms, like the electron-withdrawing substituents, reduce the π-electron density on the carbonyl carbon and stabilize the anion, formed on attack of the nucleophile, by accommodating the –ve charge.

Mechanism

The reaction completes in two-step
In first step, the nucleophile (Nu⁻) attacks the electrophilic carbonyl carbon, forming a new bond between the nucleophile and the carbon, while the electrons from the carbon-oxygen double bond move to the oxygen atom, resulting in a tetrahedral intermediate with a negative charge on the oxygen (alkoxide ion) followed by protonation (E⁺) by an acid or solvent, yielding the final addition product in the second step.

Strong nucleophiles (anionic) add directly to the >C=O to form the intermediate alkoxide. The alkoxides then protonated on work-up with dilute acid.

Weaker nucleophiles (neutral) require that the >C=O be activated prior to attack of the Nucleophile. This can be done using an acid catalyst which protonates on the Lewis basic O and makes the molecule more electrophilic.

Addition of HCN to Carbonyl Group

Addition of HCN to carbonyl group is catalysed by both, acids and bases. However, base-catalysed nucleophilic addition reactions are common. In both acid- and base-catalysed additions, the nucleophile is added in the slowest step and hence the reaction is called nucleophilic addition.

Base-catalysed Addition: The base removes the weakly acidic protons from the reagent to generate the nucleophile which adds to the carbonyl carbon in the first step. In the second step, a fast addition of protons to the negatively charged oxygen completes the addition.

Acid-catalysed Addition: The acid protonates the negatively charged oxygen atom in the first step. The slow attack of the reagent to the carbonyl carbon in the second step completes the addition.

Although acids increase the cationoid character of the carbonyl carbon, it reduces the concentration of the nucleophile. Hence, highly acidic medium retards the reaction.

Addition of Alcohol to Carbonyl Group

The addition of alcohol to carbonyl group to form hemiacetal or hemiketal is catalysed by both base and acid but the formation of acetal or ketal from hemiacetal or hemiketal is catalysed by acids only. The formation of hemiacetal or hemiketal depends uopn the carbonyl compound taken. Hemiacetal forms from aldehyde and hemiketal from ketone.

Addition of Grignard Reagent to Carbonyl Group

Grignard reagents (R-Mg-X) are polar in nature, they attribute a partial negative charge to carbon atoms and therefore they act as nucleophiles. The reaction mechanism involves an attack of nucleophiles on the carbonyl atom. Tetrahedral alkoxide intermediate is formed and in the final step, the required product is yielded.

Stereochemistry of Nucleophilic Addition to Carbonyl Group

The molecule is flat as the carbon is sp²-hybridized. Since both the sides are equivalent, the nucleophile is free to approach the carbon from either side of the plane to produce a racemic mixture.

When the carbonyl group of ketones has an asymmetric α-carbon, the two sides of the flat carbonyl compound are no longer equivalent. The bulky oxygen atom orients itself so that it is farthest from the largest of the three groups on the α-carbon.

Addition to Activated Carbon–Carbon Double Bond

Compounds containing carbon–carbon double bond conjugated with electron-withdrawing substituents undergo nucleophilic addition. Electron-withdrawing substituents reduce the π-electron density to promote nucleophilic attack and stabilize the intermediate carbanion by delocalization of the –ve charge. Thus, nucleophilic additions are observed in αβ-unsaturated aldehydes, ketones, esters, nitriles, etc. The reactions are often catalysed by base. The base converts the nucleophile (HNu) to a stronger nucleophile (Nu⁻).

Mechanism

The nucleophile attacks the β-carbon. The negative charge in the resulting carbanion is delocalized by the carbonyl group. Subsequent protonation completes the addition. Protonation occurs chiefly on the oxygen because it is more negative than the carbon. Therefore, an overall 1,4-addition occurs, which transforms into αβ-addition product. Considering the steric and electronic factors the electron-withdrawing effect decreases in the order CHO > COR > COOR > CN > NO₂ etc.

Addition of C=C vs C=O

When C=C and C=O groups are conjugated, it is seen that the addition is usually to C=C as C=O bond is stronger than C=C bond. This may be explained on the stabilities of the products formed on addition to these bonds. The product on addition to C=C has a residual C=O while the product on addition to C=O has a residual C=C.

However, steric hindrance may be an important factor. Thus, PhMgBr adds to C=O in Ph-CH=CH-CHO while the addition is to C=C in Ph-CH=CH-COCMe₃. The inductive effect of Me group may also be a factor besides steric hindrance.

Source: Reactions, Rearrangements and Reagents By S.N.Sanyal