19.13 Conjugate Nucleophilic Addition to α,β‑Unsaturated Aldehydes and Ketones
4 min read•may 7, 2024
Conjugate nucleophilic addition is a key reaction in organic synthesis. It allows us to add nucleophiles to the of α,β-unsaturated aldehydes and ketones, creating new carbon-carbon bonds. This process forms β-substituted products through an intermediate.
Understanding the factors that influence conjugate vs direct addition is crucial. The nature of the nucleophile, substrate structure, and reaction conditions all play a role in determining whether 1,4 or 1,2 addition occurs. This knowledge helps predict and control reaction outcomes in synthesis.
Conjugate Nucleophilic Addition to α,β-Unsaturated Aldehydes and Ketones
Mechanism of conjugate nucleophilic addition
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- Conjugate nucleophilic addition involves the addition of a nucleophile to the β-carbon of an α,β-unsaturated aldehyde or ketone
- The β-carbon is the carbon adjacent to the group and part of the C=C double bond ()
- The nucleophile attacks the electrophilic β-carbon, forming a new bond between the nucleophile and the β-carbon
- Nucleophiles can include amines, thiols, and organometallic reagents (, , )
- The of the attacking species affects the rate of this step
- This attack results in the formation of a resonance-stabilized intermediate
- The has a negative charge distributed between the and the oxygen of the carbonyl group
- The resonance stabilization of the enolate ion makes it a relatively stable intermediate
- The enolate ion intermediate is then protonated by an acid at the α-carbon
- Common proton sources include the solvent (protic solvents like methanol or water) or an added acid (acetic acid)
- This protonation step regenerates the carbonyl group and results in the formation of a β-substituted aldehyde or ketone product ( from cinnamaldehyde and methylmagnesium bromide)
Conjugate vs direct addition
- Conjugate (1,4) addition and direct (1,2) addition are two competing reaction pathways for nucleophilic addition to α,β-unsaturated aldehydes and ketones
- Conjugate (1,4) addition involves the nucleophile attacking the β-carbon (carbon 4 in the chain)
- Direct (1,2) addition involves the nucleophile attacking the carbonyl carbon (carbon 1 in the chain)
- The preferred reaction pathway depends on the nature of the nucleophile and the reaction conditions
- Factors influencing the preference include the hardness/softness of the nucleophile and the steric hindrance around the carbonyl group
- Amines and water tend to favor direct (1,2) addition
- These nucleophiles are hard bases and preferentially attack the electrophilic carbonyl carbon
- Primary and secondary amines (methylamine, diethylamine) and water often lead to the formation of imines, enamines, or hydrates via 1,2 addition
- Organocopper reagents favor conjugate (1,4) addition
- Organocopper reagents are soft nucleophiles and preferentially attack the softer electrophilic β-carbon
- () and other organocuprates (, ) selectively undergo 1,4 addition
- The addition of organocopper reagents is often referred to as the
Factors Affecting Conjugate Addition
- : The outcome of can be influenced by reaction conditions
- Kinetic control often favors 1,2 addition, while thermodynamic control tends to favor 1,4 addition
- : This concept helps explain the of nucleophilic addition
- Hard nucleophiles prefer to attack hard electrophilic centers (carbonyl carbon)
- Soft nucleophiles prefer to attack soft electrophilic centers (β-carbon)
- Regioselectivity: The preference for 1,2 vs. 1,4 addition is determined by various factors
- Nucleophile nature, substrate structure, and reaction conditions all play a role in determining regioselectivity
Applications of conjugate addition
- reactions can be used to synthesize β-substituted aldehydes and ketones by adding a nucleophile to the β-carbon of an α,β-unsaturated aldehyde or ketone
- To predict the product of a conjugate addition reaction:
- Identify the nucleophile and the α,β-unsaturated aldehyde or ketone
- Example: methylmagnesium bromide and cinnamaldehyde
- Determine the preferred reaction pathway (1,4 or 1,2 addition) based on the nature of the nucleophile
- Methylmagnesium bromide, an organometallic reagent, favors 1,4 addition
- Draw the structure of the enolate ion intermediate formed after the nucleophilic attack
- The enolate ion will have a negative charge on the α-carbon and the carbonyl oxygen
- Protonate the enolate ion at the α-carbon to obtain the final β-substituted aldehyde or ketone product
- Protonation of the enolate ion leads to the formation of 3-phenylbutanal
- Identify the nucleophile and the α,β-unsaturated aldehyde or ketone
- When proposing synthetic routes using conjugate addition reactions:
- Identify the target β-substituted aldehyde or ketone
- Target molecule:
- Retrosynthetically disconnect the bond formed during the conjugate addition step to obtain the α,β-unsaturated aldehyde or ketone and the nucleophile
- Disconnection reveals the starting materials: and
- Select an appropriate nucleophile that will favor conjugate (1,4) addition
- Organomagnesium reagents (Grignard reagents) like 4-methoxyphenylmagnesium bromide favor 1,4 addition
- Consider any additional steps required to prepare the α,β-unsaturated aldehyde or ketone or to further transform the β-substituted product
- The Grignard reagent can be prepared from and magnesium metal
- The product may require further purification or functional group transformations depending on the desired final compound
- Identify the target β-substituted aldehyde or ketone
Key Terms to Review (37)
1,2-Addition: 1,2-Addition is a type of organic reaction where an electrophile or nucleophile adds to the first and second carbon atoms of a conjugated diene, resulting in the formation of a new carbon-carbon bond. This term is particularly relevant in the context of electrophilic additions to conjugated dienes, kinetic versus thermodynamic control of reactions, and conjugate nucleophilic additions to α,β-unsaturated aldehydes and ketones.
1,4-Addition: 1,4-Addition is a type of electrophilic addition reaction that occurs on conjugated dienes, where the electrophile adds to the 1- and 4-positions of the diene, forming a new product with an allylic carbocation intermediate. This reaction is important in the context of understanding electrophilic additions to conjugated systems, kinetic versus thermodynamic control of reactions, and conjugate nucleophilic additions to α,β-unsaturated carbonyl compounds.
3-(4-methoxyphenyl)cyclohexanone: 3-(4-methoxyphenyl)cyclohexanone is an organic compound consisting of a cyclohexanone ring with a 4-methoxyphenyl substituent at the 3-position. This term is particularly relevant in the context of conjugate nucleophilic addition to α,β‑unsaturated aldehydes and ketones.
3-phenylbutanal: 3-phenylbutanal is an organic compound that consists of a butanal (4-carbon aldehyde) structure with a phenyl group attached at the third carbon position. It is an important intermediate in organic synthesis and has applications in the fragrance and flavor industries.
4-bromoanisole: 4-bromoanisole is an organic compound consisting of a benzene ring with a bromine atom and a methoxy group (OCH3) attached at the 4-position. It is a useful intermediate in organic synthesis and has applications in various industries.
4-methoxyphenylmagnesium bromide: 4-methoxyphenylmagnesium bromide is an organometallic compound that serves as a nucleophilic reagent in organic chemistry. It is commonly used in conjugate nucleophilic addition reactions, particularly with α,β-unsaturated aldehydes and ketones.
Carbonyl: The carbonyl group is a functional group consisting of a carbon atom double-bonded to an oxygen atom. It is a key structural feature in many organic compounds, including aldehydes, ketones, carboxylic acids, and esters, and plays a crucial role in their chemical reactivity and properties.
Cinnamaldehyde: Cinnamaldehyde is an organic compound found in cinnamon that contains an $\alpha,\beta$-unsaturated aldehyde functional group. This structural feature makes cinnamaldehyde an important compound in the context of conjugate nucleophilic addition reactions and aldol reactions in organic synthesis.
Conjugate addition: Conjugate addition is a type of nucleophilic addition reaction where a nucleophile adds to the β-carbon of an α,β-unsaturated aldehyde or ketone. This process expands the molecule by forming a new carbon-carbon bond, effectively incorporating the nucleophile into the molecule.
Conjugate Addition: Conjugate addition is a type of nucleophilic addition reaction where a nucleophile adds to the β-carbon of an α,β-unsaturated carbonyl compound, rather than the carbonyl carbon. This results in the formation of a new carbon-carbon bond and the addition of the nucleophile to the conjugated system.
Cyclohex-2-en-1-one: Cyclohex-2-en-1-one is a cyclic enone compound, consisting of a six-membered carbon ring with a ketone group at one position and a carbon-carbon double bond at an adjacent position. This structural feature makes it a key reactant in the context of conjugate nucleophilic addition reactions.
Diastereomer: Diastereomers are a type of stereoisomers that are non-superimposable, non-mirror image molecules. They differ in their spatial arrangement of atoms, leading to distinct physical and chemical properties.
Diethylamine: Diethylamine is a secondary amine with the chemical formula (CH3CH2)2NH. It is a colorless, flammable liquid with a strong, fishy odor. Diethylamine is an important organic compound that finds applications in various chemical reactions, particularly in the context of conjugate nucleophilic addition to α,β-unsaturated aldehydes and ketones.
Enolate: An enolate is a negatively charged oxygen-containing species that arises from the removal of a proton from the α-carbon of a carbonyl compound. Enolates are important reactive intermediates in various organic reactions, including aldol condensations, Claisen condensations, and α-substitution reactions.
Enolate ion: An enolate ion is a negatively charged intermediate formed from the deprotonation of an alpha carbon adjacent to a carbonyl group in aldehydes and ketones. It plays a crucial role in various organic reactions, including nucleophilic addition and substitution reactions.
Enolate Ion: An enolate ion is a type of conjugate base formed when the alpha hydrogen of a carbonyl compound is removed, resulting in a negatively charged oxygen atom adjacent to a carbon-carbon double bond. This reactive intermediate is a key player in various organic reactions, including conjugate nucleophilic additions, reactions of carboxylic acids, and carbonyl condensation reactions.
Ethanethiol: Ethanethiol, also known as ethyl mercaptan, is an organic compound with the chemical formula CH3CH2SH. It is a colorless, flammable liquid with a strong, unpleasant odor often described as resembling rotten eggs. Ethanethiol is an important compound in the context of conjugate nucleophilic addition to α,β‑unsaturated aldehydes and ketones.
Gilman Reagents: Gilman reagents, also known as organocopper reagents, are a class of organometallic compounds containing copper that are used as powerful nucleophiles in organic synthesis, particularly in conjugate addition reactions to α,β-unsaturated carbonyl compounds.
Hard-Soft Acid-Base Theory: The hard-soft acid-base (HSAB) theory is a concept in chemistry that describes the reactivity and stability of chemical species based on their relative hardness or softness. It provides a framework for understanding the preferences and tendencies of acids and bases to form stable complexes with each other.
Kinetic vs. Thermodynamic Control: Kinetic control and thermodynamic control are two important concepts in organic chemistry that describe the factors influencing the outcome of a chemical reaction. Kinetic control refers to the reaction pathway that leads to the kinetically favored product, while thermodynamic control refers to the pathway that leads to the thermodynamically stable product.
Lithium Dialkylcuprate: Lithium dialkylcuprates are organometallic reagents that serve as powerful nucleophiles in organic synthesis, particularly in the context of conjugate nucleophilic addition reactions to α,β-unsaturated aldehydes and ketones.
Methylcopper: Methylcopper is an organometallic compound consisting of a copper atom bonded to a methyl group. It is a key reagent used in conjugate nucleophilic addition reactions involving α,β-unsaturated aldehydes and ketones.
Methylmagnesium bromide: Methylmagnesium bromide, also known as Grignard reagent, is an organometallic compound that is widely used in organic chemistry for the formation of carbon-carbon bonds through nucleophilic addition reactions. It is a key reagent in various transformations, including the hydration of aldehydes and ketones, the conjugate addition to α,β-unsaturated carbonyl compounds, and the synthesis of esters.
Michael Addition: The Michael addition is a type of conjugate addition reaction where a nucleophile adds to the β-carbon of an α,β-unsaturated carbonyl compound, forming a new carbon-carbon bond. This reaction is a crucial step in many organic synthesis pathways, particularly in the context of conjugate nucleophilic addition to α,β‑unsaturated aldehydes and ketones, as well as carbonyl condensations with enamines.
Michael reaction: The Michael reaction is a nucleophilic addition of a carbanion to an α,β-unsaturated carbonyl compound. It results in the formation of a carbon-carbon bond, expanding the carbon skeleton of organic molecules.
Michael Reaction: The Michael reaction is a type of conjugate addition reaction where a nucleophile adds to the β-carbon of an α,β-unsaturated carbonyl compound, forming a new carbon-carbon bond. This reaction is named after the German chemist Arthur Michael, who first reported it in 1887.
Nucleophilicity: Nucleophilicity refers to the ability of a species to donate electrons and form a covalent bond with an electrophilic center. It is a key concept in organic chemistry that governs the reactivity and selectivity of many important reactions, including substitution, addition, and elimination reactions.
Organocuprate: An organocuprate is an organocopper compound that acts as a powerful nucleophile in organic reactions. These species are commonly used in conjugate addition reactions to $\alpha,\beta$-unsaturated carbonyl compounds.
Phenylcopper: Phenylcopper is an organometallic compound consisting of a copper atom bonded to a phenyl group. It is an important reagent in organic chemistry, particularly in the context of conjugate nucleophilic addition reactions to α,β-unsaturated aldehydes and ketones.
Regioselectivity: Regioselectivity refers to the preference of a chemical reaction to occur at a specific site or region of a molecule, leading to the formation of one regioisomeric product over another. This concept is particularly important in the context of electrophilic addition reactions of alkenes, electrophilic aromatic substitution, and other organic transformations.
Resonance-Stabilized Carbanion: A resonance-stabilized carbanion is a type of carbanion, which is a negatively charged carbon atom, that is stabilized by the delocalization of the negative charge through resonance. This allows the carbanion to be more stable and reactive in organic chemistry reactions.
Robinson Annulation: The Robinson annulation is a powerful synthetic method used to construct cyclic compounds, particularly cyclohexenones, from acyclic precursors. It involves a conjugate addition-aldol reaction sequence that allows for the efficient construction of complex molecular scaffolds.
Robinson annulation reaction: The Robinson annulation reaction is a chemical process that combines an aldol condensation with a Michael addition to construct ring systems, particularly useful in synthesizing cyclohexenones. It's a pivotal method in organic chemistry for building complex molecular structures from simpler compounds.
Stereocenter: A stereocenter is a carbon atom in a molecule that is bonded to four different substituents, resulting in a chiral center that can exist in two non-superimposable mirror-image forms called enantiomers. Stereocenters are central to understanding the handedness and configuration of molecules, as well as their interactions in biological systems.
α-carbon: The α-carbon is the carbon atom that is directly bonded to a carbonyl group (C=O) in organic compounds. It is a crucial structural feature that plays a significant role in various reactions and transformations involving carbonyl-containing molecules.
α,β-Unsaturated Carbonyl: An α,β-unsaturated carbonyl is a carbonyl compound (such as an aldehyde or ketone) that contains a carbon-carbon double bond adjacent to the carbonyl group. This structural feature has important implications in organic chemistry, particularly in the context of conjugate nucleophilic additions, aldol reactions, and other carbonyl condensation reactions.
β-carbon: The β-carbon is the carbon atom that is positioned two atoms away from a functional group or other point of interest in an organic molecule. It plays a crucial role in the reactivity and behavior of certain organic reactions, particularly in the context of conjugate nucleophilic additions and the Michael reaction.