Conjugate Addition: Videos & Practice Problems

Conjugate addition, also known as 1,4-addition, is a reaction where a nucleophile adds to the β-carbon of an α,β-unsaturated carbonyl compound (enone). This process involves the nucleophile attacking the electrophilic carbon at the 4-position, resulting in the addition across the conjugated system. This type of addition is common with nucleophiles like cyanide (CN^-) and lithium dialkylcuprate (R₂CuLi). Conjugate addition is significant in organic synthesis as it allows for the formation of complex molecules, such as 1,5-dicarbonyls, which can further cyclize to form six-membered rings.

1,2-Addition and 1,4-addition refer to the positions where nucleophiles attack an enone. In 1,2-addition, the nucleophile attacks the carbonyl carbon (position 2), leading to the formation of a substituted alcohol. This type of addition is favored by strong nucleophiles like Grignard reagents (RMgX) and organolithiums (RLi). In contrast, 1,4-addition, or conjugate addition, involves the nucleophile attacking the β-carbon (position 4) of the enone. This is favored by weaker nucleophiles such as cyanide (CN^-) and lithium dialkylcuprate (R₂CuLi), resulting in the addition across the conjugated system.

Common nucleophiles used in conjugate addition reactions include cyanide (CN^-), lithium dialkylcuprate (R₂CuLi), and enamines. These nucleophiles are less reactive compared to strong nucleophiles like Grignard reagents and organolithiums, making them suitable for attacking the β-carbon (position 4) of α,β-unsaturated carbonyl compounds (enones). Additionally, enolates and enamines are used in specific conjugate addition reactions such as the Michael reaction and Stork enamine synthesis, respectively, to form 1,5-dicarbonyl compounds.

A Michael reaction is a type of conjugate addition where an enolate ion acts as the nucleophile and adds to the β-carbon of an α,β-unsaturated carbonyl compound (enone). This reaction results in the formation of a 1,5-dicarbonyl compound. The Michael reaction is significant in organic synthesis because the 1,5-dicarbonyl products can undergo further reactions, such as cyclization, to form six-membered rings. This reaction is a key method for forming carbon-carbon bonds and constructing complex molecular architectures.

Stork enamine synthesis is a method in organic chemistry where an enamine acts as a nucleophile in a conjugate addition reaction. The enamine attacks the β-carbon of an α,β-unsaturated carbonyl compound (enone), resulting in the formation of a 1,5-dicarbonyl compound. This reaction is similar to the Michael reaction but uses an enamine instead of an enolate. The 1,5-dicarbonyl products formed can further cyclize to form six-membered rings, making Stork enamine synthesis a valuable tool for constructing complex molecules in organic synthesis.