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Organic Chemistry
Table of Contents
Unit 19 Overview: Aldehydes & Ketones: Nucleophilic Addition
19.1 Naming Aldehydes and Ketones
19.2 Preparing Aldehydes and Ketones
19.3 Oxidation of Aldehydes and Ketones
19.4 Nucleophilic Addition Reactions of Aldehydes and Ketones
19.5 Nucleophilic Addition of H2O: Hydration
19.6 Nucleophilic Addition of HCN: Cyanohydrin Formation
19.7 Nucleophilic Addition of Hydride and Grignard Reagents: Alcohol Formation
19.8 Nucleophilic Addition of Amines: Imine and Enamine Formation
19.9 Nucleophilic Addition of Hydrazine: The Wolff–Kishner Reaction
19.10 Nucleophilic Addition of Alcohols: Acetal Formation
19.11 Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction
19.12 Biological Reductions
19.13 Conjugate Nucleophilic Addition to α,β‑Unsaturated Aldehydes and Ketones
19.14 Spectroscopy of Aldehydes and Ketones

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19.4 Nucleophilic Addition Reactions of Aldehydes and Ketones

Citation:

Nucleophilic addition reactions are key players in organic chemistry. They involve electron-rich species attacking the carbonyl carbon in aldehydes and ketones. This process creates new bonds and can lead to the formation of various important compounds.

Understanding these reactions is crucial for grasping how organic molecules transform. Factors like nucleophile strength, carbonyl compound structure, and substituent effects all influence reactivity. This knowledge helps predict and control chemical outcomes in synthesis and biological processes.

Nucleophilic Addition Reactions

Mechanism of nucleophilic addition reactions

  • Nucleophilic addition reactions involve the addition of a nucleophile (electron-rich species) to the electrophilic carbonyl carbon of an aldehyde or ketone
    • The carbonyl carbon is electrophilic due to the polarization of the carbon-oxygen double bond which results in a partial positive charge on the carbon atom, making it susceptible to nucleophilic attack (e.g., by amines, alcohols, or hydride ions)
  • The reaction proceeds through a two-step mechanism:
    1. Nucleophilic attack: The nucleophile 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)
    2. Protonation: The negatively charged oxygen atom of the tetrahedral intermediate is protonated by an acid or solvent (e.g., water or alcohol), yielding the final addition product and restoring the oxygen to its neutral state, completing the nucleophilic addition reaction
  • The strength of the nucleophile, known as its nucleophilicity, plays a crucial role in determining the rate and success of the addition reaction

Aldehydes vs ketones in reactivity

  • Aldehydes are generally more reactive than ketones in nucleophilic addition reactions due to both steric and electronic factors
    • Steric factors: Aldehydes have only one substituent (hydrogen) attached to the carbonyl carbon, while ketones have two (alkyl or aryl groups), creating more steric hindrance around the carbonyl carbon in ketones, making it less accessible to nucleophilic attack
    • Electronic factors: The carbonyl carbon in aldehydes is more electrophilic than in ketones because the two alkyl groups attached to the carbonyl carbon in ketones donate electron density through hyperconjugation, making the carbonyl carbon less electrophilic and less reactive towards nucleophiles
  • The combination of reduced steric hindrance and increased electrophilicity makes aldehydes more reactive than ketones in nucleophilic addition reactions (e.g., addition of Grignard reagents or reduction by LiAlH4)

Substituent Effects on Reactivity

Substituent effects on carbonyl reactivity

  • Substituents can affect the reactivity of carbonyl compounds by altering the electrophilicity of the carbonyl carbon through electronic effects
    • Electron-withdrawing groups (EWGs) increase the reactivity of carbonyl compounds by pulling electron density away from the carbonyl carbon, making it more electrophilic and more susceptible to nucleophilic attack (e.g., halogens, nitro, and cyano groups)
    • Electron-donating groups (EDGs) decrease the reactivity of carbonyl compounds by pushing electron density towards the carbonyl carbon, making it less electrophilic and less susceptible to nucleophilic attack (e.g., alkyl, hydroxyl, and amino groups)
  • Aromatic aldehydes, such as benzaldehyde, are less reactive than aliphatic aldehydes because the benzene ring is an electron-rich system that donates electron density to the carbonyl carbon through resonance, making it less electrophilic and less reactive
  • Substituted benzaldehydes can have different reactivities depending on the nature and position of the substituents
    • Electron-withdrawing substituents on the benzene ring (e.g., $-$NO$_2$, $-$Cl) increase the reactivity of the carbonyl carbon by further withdrawing electron density
    • Electron-donating substituents on the benzene ring (e.g., $-$OH, $-$NH$_2$) decrease the reactivity of the carbonyl carbon by donating additional electron density

Common Nucleophilic Addition Reactions

  • Hydration is a common carbonyl addition reaction where water acts as the nucleophile, forming a geminal diol (hydrate)
  • Cyanohydrin formation occurs when cyanide ions act as nucleophiles, producing compounds with a hydroxyl and nitrile group on the same carbon
  • Imine formation involves the reaction of primary amines with aldehydes or ketones, resulting in a carbon-nitrogen double bond

Key Terms to Review (27)

Alkoxide ion, RO–: An alkoxide ion is the conjugate base of an alcohol, formed by the deprotonation of the hydroxyl group (OH) in an alcohol molecule, resulting in a negatively charged oxygen atom bonded to an alkyl group (R). It plays a crucial role in various organic reactions, especially as a strong nucleophile.
β Diketone: A β-diketone is an organic compound containing two ketone groups separated by a carbon atom, which is the beta (β) position relative to each ketone group. These molecules are characterized by the presence of hydrogen atoms on the carbon between the two carbonyl (C=O) groups, making them acidic and prone to enolate ion formation.
Nucleophilic addition reaction: A nucleophilic addition reaction is a chemical process where a nucleophile forms a bond with an electrophilic carbon atom of a compound, typically found in aldehydes and ketones. This reaction results in the conversion of the carbonyl group into a more complex, often larger, molecule.
Resonance: Resonance is a fundamental concept in organic chemistry that describes the ability of certain molecules to exist in multiple equivalent structures or resonance forms. This phenomenon arises from the delocalization of electrons within the molecule, leading to the stabilization of the overall structure and the distribution of electron density across multiple atoms.
Electrophilic: Electrophilic refers to a species or reagent that is attracted to or seeks out electron-rich regions, typically in organic chemistry reactions. These species are often positively charged or have a partial positive charge, and they interact with and form bonds with nucleophiles, which are electron-rich species.
Hyperconjugation: Hyperconjugation is a type of conjugation in organic chemistry where the sigma bonds of alkyl groups (such as methyl or ethyl) interact with adjacent pi bonds, leading to increased stability of the molecule. This stabilizing effect is particularly important in understanding the stability of carbocations and the orientation of electrophilic additions.
Grignard Reagent: A Grignard reagent is an organometallic compound consisting of an alkyl or aryl group bonded to a magnesium atom. These versatile reagents are widely used in organic synthesis to form new carbon-carbon bonds and introduce various functional groups, making them an essential tool in the preparation of alcohols from carbonyl compounds.
Nucleophilic Addition: Nucleophilic addition is a fundamental organic reaction in which a nucleophile, a species that donates electrons, adds to an electrophilic carbon center, typically a carbonyl carbon, to form a new product. This reaction is central to understanding many important topics in organic chemistry, including functional groups, polar reactions, carbocation stability, reaction stereochemistry, and the chemistry of aldehydes, ketones, alcohols, and other carbonyl-containing compounds.
Benzaldehyde: Benzaldehyde is an aromatic aldehyde compound with the chemical formula C6H5CHO. It is a colorless liquid with a characteristic almond-like odor and is widely used in the production of various organic compounds, including pharmaceuticals, flavors, and fragrances.
Aldehyde: An aldehyde is a class of organic compounds containing a carbonyl group (C=O) where the carbon atom is bonded to one hydrogen atom and one alkyl or aryl group. Aldehydes are important functional groups in organic chemistry and are involved in various reactions and synthesis pathways.
Ketone: A ketone is a functional group in organic chemistry that consists of a carbonyl group (a carbon-oxygen double bond) bonded to two alkyl or aryl groups. Ketones are widely encountered in various organic chemistry topics, including the hydration of alkynes, oxidative cleavage of alkynes, organic synthesis, oxidation and reduction reactions, and the chemistry of aldehydes and ketones.
Steric Hindrance: Steric hindrance, also known as steric strain or steric effect, refers to the repulsive forces that arise between atoms or groups of atoms in a molecule due to their physical size and spatial arrangement. This phenomenon can significantly impact the stability, reactivity, and conformations of organic compounds.
Hydration: Hydration is the process of adding water to a chemical compound, typically involving the addition of water across a double bond or the incorporation of water into the structure of a molecule. This term is particularly relevant in the context of organic chemistry, where it plays a crucial role in various reactions and transformations.
Nucleophile: A nucleophile is a species that donates a pair of electrons to form a covalent bond with another atom or molecule. Nucleophiles are central to understanding many organic reactions, including polar reactions, electrophilic addition reactions, and nucleophilic substitution reactions.
Electron-Donating Group: An electron-donating group is a functional group or substituent in a molecule that has the ability to donate or share its electrons with other atoms or groups, typically to stabilize a positive charge or increase the electron density in a specific region of the molecule. This term is particularly relevant in the context of understanding carbocation stability and nucleophilic addition reactions of aldehydes and ketones.
Electron-Withdrawing Group: An electron-withdrawing group is a functional group or substituent in a molecule that has the ability to attract or withdraw electrons from the surrounding atoms, thereby stabilizing or destabilizing certain reaction intermediates or transition states. This property plays a crucial role in understanding carbocation stability, nucleophilic aromatic substitution, and nucleophilic addition reactions of aldehydes and ketones.
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.
Electrophilicity: Electrophilicity is a measure of the affinity of a species for electron density, reflecting its ability to attract and bond with electrons. This term is particularly relevant in the context of electrophilic substitution reactions and the nucleophilic addition reactions of aldehydes and ketones.
Tetrahedral Intermediate: A tetrahedral intermediate is a key reaction step that occurs in many organic chemistry reactions, where a trigonal planar carbonyl carbon temporarily becomes a tetrahedral carbon with four bonded atoms. This transient intermediate is crucial for understanding the mechanisms of various nucleophilic addition and substitution reactions.
Alkoxide Ion: An alkoxide ion is a negatively charged species formed when an alkyl group (R-) is bonded to an oxygen atom. It is a key intermediate in various organic chemistry reactions, including the preparation of ethers, nucleophilic addition reactions of aldehydes and ketones, and the hydration of carboxylic acids.
Cyanohydrin Formation: Cyanohydrin formation is a nucleophilic addition reaction that occurs between an aldehyde or ketone and hydrogen cyanide (HCN), resulting in the formation of a cyanohydrin product. This reaction is an important tool in organic chemistry for the synthesis of various compounds.
LiAlH4: LiAlH4, also known as lithium aluminum hydride, is a powerful reducing agent commonly used in organic chemistry reactions. It is particularly useful in the context of nucleophilic addition reactions of aldehydes and ketones, the chemistry of esters and amides, as well as the synthesis of amines.
Aliphatic Aldehyde: An aliphatic aldehyde is a type of organic compound that contains a carbonyl group (C=O) bonded to at least one hydrogen atom and an alkyl group. These aldehydes are characterized by their linear or branched carbon chain structure, as opposed to aromatic aldehydes which have a cyclic structure.
Carbonyl Addition: Carbonyl addition is a fundamental organic reaction where a nucleophile adds to the carbon atom of a carbonyl group, typically an aldehyde or ketone, to form a new carbon-carbon or carbon-heteroatom bond. This process is a crucial aspect of understanding the reactivity and synthesis of carbonyl compounds.
Imine Formation: Imine formation is a chemical reaction in which a primary amine (R-NH2) reacts with an aldehyde or ketone to produce an imine (R-N=CR'R''), also known as a Schiff base. This process is a key step in numerous organic chemistry reactions, particularly in the context of nucleophilic addition reactions of aldehydes and ketones, as well as the nucleophilic addition of amines to form imines and enamines.
Aromatic Aldehyde: An aromatic aldehyde is a type of organic compound that contains an aldehyde functional group (-CHO) attached directly to an aromatic ring, such as a benzene ring. These compounds exhibit the characteristic properties of both aldehydes and aromatic compounds.
Carbonyl group: A carbonyl group is a functional group characterized by a carbon atom double-bonded to an oxygen atom, represented as C=O. This group is pivotal in organic chemistry as it forms the backbone of various important classes of compounds, influencing their chemical properties and reactivity.