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Aldehydes and Ketones
Nucleophilic Addi3on Reac3ons
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• Aldehydes (RCHO) and ketones (R2CO) are characterized by the carbonyl func3onal group (C=O)
• The compounds occur widely in nature as intermediates in metabolism and biosynthesis
Aldehydes and Ketones
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Aldehydes and Ketones
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Nomenclature of Aldehydes
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Naming the Aldehyde as a Subs3tuent
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• Replace the terminal -‐e of the alkane name with –one • Parent chain is the longest one that contains the ketone group
– Numbering begins at the end nearer the carbonyl carbon
Naming Ketones
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• IUPAC retains well-‐used but unsystema3c names for a few ketones
Ketones with Common Names
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Nomenclature of Ketones
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• The R–C=O as a subs3tuent is an acyl group, used with the suffix -‐yl from the root of the carboxylic acid – CH3CO: acetyl; CHO: formyl; C6H5CO: benzoyl
• The prefix oxo-‐ is used if other func3onal groups are present and the doubly bonded oxygen is labeled as a subs3tuent on a parent chain
Ketones and Aldehydes as Subs3tuents
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Reac3vity of Aldehydes and Ketones
Electronic Reasoning: • An aldehyde has a greater partial positive
charge on its carbonyl carbon than does a ketone.
• Because a hydrogen is more electron withdrawing than an alkyl group.
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Aldehydes are More Reac3ve than Ketone
• Ketones have greater steric crowding in their transi3on states, so they have less stable transi3on states than do aldehydes.
• The carbonyl carbon of an aldehyde is more accessible to the nucleophile.
Reac3vity of Carbonyl Groups
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Preparing Aldehydes and Ketones
• From Alkenes (Ozonolysis) • From Alkynes Aldehyde from terminal alkyne via Hydrobra3on
Ketone from symmetrical alkyne via Hydrobora3on and Mercury2+
catalyzed hydra3on
• From Alcohols (Aldehyde and Ketone • From Arene (ketones from Friedel-‐Craas acyla3on)
• From Carbonyl Chemistry
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From Various Carbonyls
R H
O
R R'
OHH
R R'
O
1) R'Li
2) H2O
O
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• CrO3 in aqueous acid oxidizes aldehydes to carboxylic acids efficiently
• Silver oxide, Ag2O, in aqueous ammonia (Tollens’ reagent) oxidizes aldehydes
Oxida3on of Aldehydes and Ketones
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• Undergo slow cleavage with hot, alkaline KMnO4 • C–C bond next to C=O is broken to give carboxylic acids • Reac3on is prac3cal for cleaving symmetrical ketones
Ketones Oxidize with Difficulty
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Oxida3on of Aldehydes and Ketones
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The Baeyer–Villiger Oxida3on
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• Nucleophiles can be nega3vely charged ( :Nu-‐) or neutral ( :Nu) at the reac3on site
• Hydride, hydroxide, organolithium, organomagnesium, acetylide, cyanide
Nucleophilic Addi3on Reac3ons of Aldehydes and Ketones
Nucleophiles
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• Aldehydes are generally more reac3ve than ketones in nucleophilic addi3on reac3ons
• The transi3on state for addi3on is less crowded and lower in energy for an aldehyde (a) than for a ketone (b)
• Aldehydes have one large subs3tuent bonded to the C=O: ketones have two
Rela3ve Reac3vity of Aldehydes and Ketones
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• Aldehyde C=O is more polarized than ketone C=O • As in carboca3ons, more alkyl groups stabilize + character • Ketone has more alkyl groups, stabilizing the C=O carbon
induc3vely
Electrophilicity of Aldehydes and Ketones
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• Less reac3ve in nucleophilic addi3on reac3ons than alipha3c aldehydes
• Electron-‐dona3ng resonance effect of aroma3c ring makes C=O less reac3ve electrophile than the carbonyl group of an alipha3c aldehyde
Reac3vity of Aroma3c Aldehydes
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• Convert C=O to CH-‐OH • LiAlH4 and NaBH4 react as donors of hydride ion • Protona3on aaer addi3on yields the alcohol
Hydride Addi3on
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Cataly3c Hydrogena3on Reduces Carbon—Oxygen Double Bonds
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• Treatment of aldehydes or ketones with Grignard reagents yields an alcohol – Nucleophilic addi3on of the equivalent of a carbon anion, or
carbanion. A carbon–magnesium bond is strongly polarized, so a Grignard reagent reacts for all prac3cal purposes as R: -‐ MgX+.
Nucleophilic Addi3on of Grignard Reagents and Organolithium Reagents: Alcohol Forma3on
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• Aldehydes and unhindered ketones react with HCN to yield cyanohydrins, RCH(OH)C≡N
• Addi3on of HCN is reversible and base-‐catalyzed, genera3ng nucleophilic cyanide ion, CN-‐
• Addi3on of CN-‐ to C=O yields a tetrahedral intermediate, which is then protonated
• Equilibrium favors adduct
Nucleophilic Addi3on of HCN: Cyanohydrin Forma3on
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• The nitrile group (⎯C≡N) can be reduced with LiAlH4 to yield a primary amine (RCH2NH2)
• Can be hydrolyzed by hot acid to yield a carboxylic acid
Uses of Cyanohydrins
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Cataly3c Hydrogena3on Reduces Carbon—Nitrogen Double and Triple
Bonds
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• Aldehyde oxida3ons occur through 1,1-‐diols (“hydrates”) • Reversible addi3on of water to the carbonyl group • Aldehyde hydrate is oxidized to a carboxylic acid by usual
reagents for alcohols
Hydra3on of Aldehydes
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• Aldehydes and ketones react with water to yield 1,1-‐diols (geminal (gem) diols)
• Hyrda3on is reversible: a gem diol can eliminate water
Nucleophilic Addi3on of H2O: Hydra3on
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• Addi3on of water is catalyzed by both acid and base
• The base-‐catalyzed hydra3on nucleophile is the hydroxide ion, which is a much stronger nucleophile than water
Base-‐Catalyzed Addi3on of Water
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• Protona3on of C=O makes it more electrophilic
Acid-‐Catalyzed Addi3on of Water
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• Alcohols are weak nucleophiles but acid promotes addi3on forming the conjugate acid of C=O
• Addi3on yields a hydroxy ether, called a hemiacetal (reversible); further reac3on can occur
• Protona3on of the –OH and loss of water leads to an oxonium ion, R2C=OR+ to which a second alcohol adds to form the acetal
Nucleophilic Addi3on of Alcohols: Acetal Forma3on
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• Acetals can serve as protec3ng groups for aldehydes and ketones
• It is convenient to use a diol to form a cyclic acetal (the reac3on goes even more readily)
Uses of Acetals
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The Reac3ons of Aldehydes and Ketones with Alcohols
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Acid-‐Catalyzed Hydrolysis of an Acetal
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The Addi3on of Sulfur Nucleophiles
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Thioacetals are Desulfurized with Hydrogen and Raney Nickel
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• Reac3on of C=O with H-‐Y, where Y is electronega3ve, gives an addi3on product (“adduct”)
• Forma3on is readily reversible
Addi3on of H–Y to C=O
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• RNH2 adds to R’2C=O to form imines, R’2C=NR (aaer loss of HOH)
• R2NH yields enamines, R2N⎯CR=CR2 (aaer loss of HOH) (ene + amine = unsaturated amine)
Nucleophilic Addi3on of Amines: Imine and Enamine Forma3on
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Aldehydes and Ketones Form Imines with Primary Amines
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• Primary amine adds to C=O
• Proton is lost from N and adds to O to yield an amino alcohol (carbinolamine)
• Protona3on of OH converts it into water as the leaving group
• Result is iminium ion, which loses proton
• Acid is required for loss of OH– too much acid blocks RNH2
Mechanism of Forma3on of Imines
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Forma3on of Imine Deriva3ves
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Imine Hydrolysis is Irreversible
• The amine is protonated in the acidic solution, so it is unable to react with the carbonyl compound.
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• Addi3on of amines with an atom containing a lone pair of electrons on the adjacent atom occurs very readily, giving useful, stable imines
• For example, hydroxylamine forms oximes and 2,4-‐dinitrophenylhydrazine readily forms 2,4-‐dinitrophenylhydrazones – These are usually solids and help in characterizing liquid ketones
or aldehydes by mel3ng points
Imine Deriva3ves
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Aldehydes and Ketones Form Enamines with Secondary Amines
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Enamine Forma3on
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• Treatment of an aldehyde or ketone with hydrazine, H2NNH2, and KOH converts the compound to an alkane
• Originally carried out at high temperatures but with dimethyl sulfoxide as solvent takes place near room temperature
Nucleophilic Addi3on of Hydrazine: The Wolff–Kishner Reac3on
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Enamine Hydrolysis is Irreversible
• The amine is protonated in the acidic solu3on, so it is unable to react with the carbonyl compound.
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Reduc3ve Amina3on
• The unstable imine formed from ammonia is hydrogenated to an amine.
• Imines and enamines are reduced to amines with NaBH3CN.
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• The sequence converts C=O to C=C • A phosphorus ylide adds to an aldehyde or ketone to yield a
dipolar intermediate called a betaine • The intermediate spontaneously decomposes through a four-‐
membered ring to yield alkene and triphenylphosphine oxide, (Ph)3P=O
• Forma3on of the ylide is shown below
Nucleophilic Addi3on of Phosphorus Ylides: The Wipg Reac3on
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Synthesizing Alkenes (The Wipg Reac3on)
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Mechanism of the Wipg Reac3on
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• Can be used for monosubs3tuted, disubs3tuted, and trisubs3tuted alkenes but not tetrasubs3tuted alkenes The reac3on yields a pure alkene of known structure
• For comparison, addi3on of CH3MgBr to cyclohexanone and dehydra3on with, yields a mixture of two alkenes
Uses of the Wipg Reac3on
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Choosing Partners for the Wipg Reac3on
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• The adduct of an aldehyde and OH-‐ can transfer hydride ion to another aldehyde C=O resul3ng in a simultaneous oxida3on and reduc3on (dispropor2ona2on)
Biological Reduc3ons
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Direct vs. Conjugate Nucleophilic Addi3on to α,β-‐Unsaturated Aldehydes and Ketones
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Kine3c and Thermodynamic Control
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• Primary and secondary amines add to α, β-‐unsaturated aldehydes and ketones to yield β-‐amino aldehydes and ketones
Conjugate Addi3on of Amines
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• Reac3on of an α,β-‐unsaturated ketone with a lithium diorganocopper reagent
• Diorganocopper (Gilman) reagents form by reac3on of 1 equivalent of cuprous iodide and 2 equivalents of organolithium
• 1°, 2°, 3° alkyl, aryl and alkenyl groups react but not alkynyl groups
Conjugate Addi3on of Alkyl Groups: Organocopper Reac3ons
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• Conjugate nucleophilic addi3on of a diorganocopper anion, R2Cu-‐, to an enone
• Transfer of an R group and elimina3on of a neutral organocopper species, RCu
Mechanism of Alkyl Conjugate Addi3on: Organocopper Reac3ons
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• Infrared Spectroscopy • Aldehydes and ketones show a strong C=O peak 1660 to 1770
cm-‐1 • aldehydes show two characteris3c C–H absorp3ons in the 2720
to 2820 cm-‐1 range.
Spectroscopy of Aldehydes and Ketones
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• Aldehyde proton signals are near δ 10 in 1H NMR -‐ dis3nc3ve spin–spin coupling with protons on the neighboring carbon, J ≈ 3 Hz
NMR Spectra of Aldehydes
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• C=O signal is at δ 190 to δ 215 • No other kinds of carbons absorb in this range
13C NMR of C=O
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• Alipha3c aldehydes and ketones that have hydrogens on their gamma (γ) carbon atoms rearrange as shown
Mass Spectrometry – McLafferty Rearrangement
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• Cleavage of the bond between the carbonyl group and the α carbon
• Yields a neutral radical and an oxygen-‐containing ca3on
Mass Spectroscopy: α-‐Cleavage
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