Ketones, Aldehydes, and Amines: Structure, Reactivity, Synthesis, and Applications

Chapter 17: Ketones & Aldehydes

NAS (Nucleophilic Aromatic Substitution)

Nucleophilic Aromatic Substitution (NAS) is a reaction where a nucleophile replaces a leaving group on an aromatic ring, typically under specific conditions. This process is less common than electrophilic aromatic substitution but is important for certain aromatic compounds.

• Key Point: NAS often requires electron-withdrawing groups ortho or para to the leaving group to stabilize the intermediate.

• Example: Substitution of a halide on nitrobenzene by hydroxide ion.

Chapter 18: Ketones & Aldehydes

Structure & Reactivity of Carbonyls

The carbonyl group (C=O) is a central functional group in organic chemistry, found in both ketones and aldehydes. Its structure and reactivity are influenced by electronic and steric factors.

• Hybridization: The carbonyl carbon is sp2 hybridized, resulting in trigonal planar geometry.

• Bonding and Resonance: The carbonyl oxygen is partially negative (δ-) and the carbon is partially positive (δ+), making the carbonyl carbon electrophilic.

• Dipole Moment: The C=O bond is strongly polarized, leading to a significant dipole moment.

• Electrophilicity: The carbonyl carbon is susceptible to nucleophilic attack due to its partial positive charge.

Oxidation/Reduction

Ketones and aldehydes can be interconverted or transformed via oxidation and reduction reactions.

• Oxidation: Aldehydes can be oxidized to carboxylic acids; ketones are generally resistant to further oxidation.

• Reduction: Both can be reduced to alcohols using hydride reagents.

Nomenclature of Aldehydes & Ketones

Systematic naming follows IUPAC rules, but common names are also widely used.

• IUPAC Rules: Aldehydes use the suffix "-al"; ketones use "-one".

• Common Names: Many simple aldehydes and ketones have trivial names (e.g., acetone, formaldehyde).

• Substituent Nomenclature: Aldehyde as substituent: "-formyl-"; ketone as substituent: "-oxo-".

• Multifunctional Nomenclature: Priority rules apply when multiple functional groups are present.

Spectroscopy

Spectroscopic techniques are essential for identifying and characterizing carbonyl compounds.

• IR Spectroscopy:

  • Strong C=O stretch around 1710 cm-1 (shifted lower with conjugation).

  • Aldehyde C-H stretches: two weak absorptions near 2720 & 2820 cm-1.

• Proton NMR:

  • Aldehyde H: δ = 9–10 ppm.

Synthesis of Aldehydes & Ketones (Old Reactions)

Several classical methods exist for synthesizing aldehydes and ketones.

• Oxidation of alcohols (PCC, Jones, Tollens, Ozonolysis, Friedel-Crafts Acylation).

• Alkyne hydration, hydride additions, Grignard reactions, acid chlorides (other reactions in multisteps).

• From nitriles: Addition of organometallic reagents, then hydrolysis.

• Nitrile hydrolysis to carboxylic acids (RCOOH).

• DIBAL-H uses for selective reduction.

Reactivity of Aldehydes vs Ketones

Aldehydes are generally more reactive than ketones due to electronic and steric factors.

• Electronic Effects: Aldehydes have only one alkyl group, making the carbonyl carbon more electrophilic.

• Steric Effects: Ketones have two alkyl groups, which hinder nucleophilic attack.

Reactions of Aldehydes & Ketones

Carbonyl compounds undergo a variety of addition and substitution reactions.

• General Addition Mechanism: Nucleophile attacks carbonyl, forming a tetrahedral intermediate, followed by protonation.

• Acid/Base Catalysis: Many reactions are catalyzed by acids or bases.

• Specific Additions:

  • Hydration (know mechanism).

  • Hemiacetal and acetal formation and hydrolysis (know mechanism).

  • Cyanohydrin formation (addition of HCN).

  • Imine formation (with primary amines), enamine formation (with secondary amines).

  • Reactions with organometallic reagents (Grignard, organolithium).

  • Reduction by hydride reagents (NaBH4, LiAlH4).

  • Use of LAH/DIBAL-H for selective reductions.

  • Wittig reaction (conversion to alkenes, know mechanism).

  • Aldol condensation (review mechanism).

  • Acid chloride formation via SOCl2 (know reaction, not mechanism).

Multistep Synthesis: Synthetic Strategy & Applications

Multistep synthesis involves planning and executing sequences of reactions to build complex molecules.

• Planning syntheses that use carbonyl intermediates.

• Retrosynthetic disconnections involving carbonyls.

• Examples of multistep syntheses using ketone/aldehyde transformations.

• Recognizing which reagents or protecting groups might be needed.

Chapter 19: Amines

Introduction & Nomenclature

Amines are nitrogen-containing organic compounds classified by the number of alkyl or aryl groups attached to the nitrogen atom.

• Classification: Primary (1°), secondary (2°), tertiary (3°), quaternary ammonium salts.

• IUPAC Naming: Rules for naming amines and common names.

• Functional Priority: Amino group vs other functional groups.

Structure, Hybridization & Basicity

The structure and basicity of amines are influenced by their electronic configuration and substituents.

• Structure: Nitrogen in amines is sp3 hybridized with a lone pair.

• Lone Pair Orientation: Pyramidal geometry.

• Stereochemistry: Inversion at nitrogen is rapid, preventing chirality.

• Basicity: Determined by pKa of conjugate acid; affected by substituents and resonance.

• Resonance Delocalization: Aromatic amines have reduced basicity due to delocalization.

• Hydridization Effects: sp3 vs sp2 vs sp hybridization affects basicity.

• Geometry: Comparison of aliphatic vs aromatic vs heterocyclic amines.

Physical Properties & Spectroscopy

Amines have characteristic physical properties and can be identified by spectroscopic methods.

• IR Spectroscopy: N-H stretches, NH bending modes.

Reactions of Amines

Amines participate in a variety of organic reactions, often as nucleophiles.

• Enamine Formation: Reaction with carbonyls (know mechanism).

• Imine Formation: Reaction with aldehydes/ketones (know mechanism).

• EAS and NAS: Electrophilic and nucleophilic aromatic substitution (review chapter 17).

• Formation of Amides: Reaction with acid chlorides (know mechanism).

• Alkylation of Amines: SN2 reactions (know mechanism).

• Hofmann Elimination: Conversion to alkenes (know mechanism).

• Reactions with Nitrous Acid: Formation of diazonium salts (know mechanism).

• Reductive Amination: Formation of amines from carbonyls (know mechanism).

• Reduction of Nitriles: Formation of amines (mechanism not required).

• Oxidation of Amines: Formation of nitroso/nitro compounds (mechanism not required).

Multistep Synthetic Strategy & Applications

Multistep synthesis with amines involves planning transformations and protecting group strategies.

• Retrosynthetic planning involving amine formation and transformations.

• Protection-deprotection strategies for amine functional groups.

• Examples combining carbonyl and amine chemistry (e.g., reductive amination).

Comparison Table: Aldehydes vs Ketones

The following table summarizes key differences between aldehydes and ketones:

Property	Aldehyde	Ketone
Structure	R-CHO (one alkyl, one H)	R-CO-R' (two alkyl groups)
Reactivity	More reactive (less steric hindrance)	Less reactive (more steric hindrance)
Oxidation	Can be oxidized to acids	Resistant to oxidation
IR C=O Stretch	~1720 cm-1	~1710 cm-1
NMR (H)	9–10 ppm (aldehyde H)	No aldehyde H

Additional info: Some mechanistic details and examples have been expanded for clarity and completeness.