Transcript Chapter 19. Aldehydes and Ketones: Nucleophilic Addition Reactions

Chapter 19. Aldehydes and
Ketones: Nucleophilic
Addition Reactions
Based on McMurry’s Organic Chemistry, 7th edition
Aldehydes and Ketones
 Aldehydes (RCHO) and ketones (R2CO) are
characterized by the the carbonyl functional group
(C=O)
 The compounds occur widely in nature as
intermediates in metabolism and biosynthesis
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Why this Chapter?
 Much of organic chemistry involves the
chemistry of carbonyl compounds
 Aldehydes/ketones are intermediates in
synthesis of pharmaceutical agents,
biological pathways, numerous industrial
processes
 An understanding of their properties is
essential
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19.1 Naming Aldehydes and
Ketones
 Aldehydes are named by replacing the terminal -e of
the corresponding alkane name with –al
 The parent chain must contain the CHO group

The CHO carbon is numbered as C1
 If the CHO group is attached to a ring, use the
suffix carbaldehyde.
 See Table 19.1 for common names
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Naming Ketones
 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
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Ketones with Common Names
 IUPAC retains well-used but unsystematic names for
a few ketones
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Ketones and Aldehydes as
Substituents
 The R–C=O as a substituent 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 functional groups are
present and the doubly bonded oxygen is labeled as a
substituent on a parent chain
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19.2 Preparation of Aldehydes and
Ketones
 Preparing Aldehydes
 Oxidize primary alcohols using pyridinium
chlorochromate
 Alkenes with a vinylic hydrogen can undergo
oxidative cleavage when treated with ozone,
yielding aldehydes
 Reduce an ester with diisobutylaluminum
hydride (DIBAH)
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Preparing Ketones
 Oxidize a 2° alcohol
 Many reagents possible: choose for the specific
situation (scale, cost, and acid/base sensitivity)
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Ketones from Ozonolysis
 Ozonolysis of alkenes yields ketones if one of the
unsaturated carbon atoms is disubstituted
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Aryl Ketones by Acylation
 Friedel–Crafts acylation of an aromatic ring with an
acid chloride in the presence of AlCl3 catalyst
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Methyl Ketones by Hydrating Alkynes
 Hydration of terminal alkynes in the presence of Hg2+
(catalyst: Section 8.4)
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19.3 Oxidation of Aldehydes and
Ketones
 CrO3 in aqueous acid oxidizes aldehydes to
carboxylic acids efficiently
 Silver oxide, Ag2O, in aqueous ammonia (Tollens’
reagent) oxidizes aldehydes (no acid)
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Hydration of Aldehydes
 Aldehyde oxidations occur through 1,1-diols
(“hydrates”)
 Reversible addition of water to the carbonyl group
 Aldehyde hydrate is oxidized to a carboxylic acid by
usual reagents for alcohols
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Ketones Oxidize with Difficulty
 Undergo slow cleavage with hot, alkaline KMnO4
 C–C bond next to C=O is broken to give carboxylic
acids
 Reaction is practical for cleaving symmetrical ketones
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19.4 Nucleophilic Addition Reactions of
Aldehydes and Ketones
 Nu- approaches 75° to the plane of C=O and adds
to C
 A tetrahedral alkoxide ion intermediate is produced
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Nucleophiles
 Nucleophiles can be negatively charged ( : Nu) or
neutral ( : Nu) at the reaction site
 The overall charge on the nucleophilic species is not
considered
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Relative Reactivity of Aldehydes
and Ketones
 Aldehydes are generally more reactive than ketones
in nucleophilic addition reactions
 The transition state for addition is less crowded and
lower in energy for an aldehyde (a) than for a ketone
(b)
 Aldehydes have one large substituent bonded to the
C=O: ketones have two
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Electrophilicity of Aldehydes and
Ketones
 Aldehyde C=O is more polarized than ketone C=O
 As in carbocations, more alkyl groups stabilize +
character
 Ketone has more alkyl groups, stabilizing the C=O
carbon inductively
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Reactivity of Aromatic Aldehydes
 Less reactive in nucleophilic addition reactions than
aliphatic aldehydes
 Electron-donating resonance effect of aromatic ring
makes C=O less reactive electrophile than the
carbonyl group of an aliphatic aldehyde
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19.5 Nucleophilic Addition of H2O:
Hydration
 Aldehydes and ketones react with water to yield 1,1-
diols (geminal (gem) diols)
 Hyrdation is reversible: a gem diol can eliminate
water
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Base-Catalyzed Addition of
Water
 Addition of water is catalyzed by
both acid and base
 The base-catalyzed hydration
nucleophile is the hydroxide ion,
which is a much stronger
nucleophile than water
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Acid-Catalyzed Addition of Water
 Protonation of C=O makes it
more electrophilic
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Addition of H-Y to C=O
 Reaction of C=O with H-Y, where Y is
electronegative, gives an addition product (“adduct”)
 Formation is readily reversible
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19.6 Nucleophilic Addition of HCN:
Cyanohydrin Formation
 Aldehydes and unhindered ketones react with HCN to yield
cyanohydrins, RCH(OH)CN
 Addition of HCN is reversible and base-catalyzed,
generating nucleophilic cyanide ion, CN Addition of CN to C=O yields a tetrahedral
intermediate, which is then protonated
 Equilibrium favors adduct
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Uses of Cyanohydrins
 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
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19.7 Nucleophilic Addition of Grignard
Reagents and Hydride Reagents: Alcohol
Formation
 Treatment of aldehydes or ketones with Grignard
reagents yields an alcohol

Nucleophilic addition of the equivalent of a carbon
anion, or carbanion. A carbon–magnesium bond is
strongly polarized, so a Grignard reagent reacts for all
practical purposes as R :  MgX +.
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Mechanism of Addition of Grignard
Reagents
 Complexation of C=O
by Mg2+, Nucleophilic
addition of R : ,
protonation by dilute
acid yields the neutral
alcohol
 Grignard additions are
irreversible because a
carbanion is not a
leaving group
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Hydride Addition
 Convert C=O to CH-OH
 LiAlH4 and NaBH4 react as donors of hydride ion
 Protonation after addition yields the alcohol
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19.8 Nucleophilic Addition of Amines:
Imine and Enamine Formation
RNH2 adds to C=O to form imines, R2C=NR (after loss of HOH)
R2NH yields enamines, R2NCR=CR2 (after loss of HOH)
(ene + amine = unsaturated amine)
“Thompson Now” (Section 19.8)
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Mechanism of Formation of
Imines
 Primary amine adds to




C=O
Proton is lost from N and
adds to O to yield a
neutral amino alcohol
(carbinolamine)
Protonation of OH
converts 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
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Imine Derivatives
 Addition 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 2,4dinitrophenylhydrazine readily forms 2,4dinitrophenylhydrazones

These are usually solids and help in characterizing
liquid ketones or aldehydes by melting points
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Enamine Formation
 After addition of R2NH,
proton is lost from
adjacent carbon
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19.9 Nucleophilic Addition of Hydrazine: The
Wolff–Kishner Reaction
 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
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19.10 Nucleophilic Addition of
Alcohols: Acetal Formation
 Alcohols are weak nucleophiles but acid promotes
addition forming the conjugate acid of C=O
 Addition yields a hydroxy ether, called a hemiacetal
(reversible); further reaction can occur
 Protonation of the OH and loss of water leads to an
oxonium ion, R2C=OR+ to which a second alcohol
adds to form the acetal
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Uses of Acetals
 Acetals can serve as protecting groups for aldehydes
and ketones
 It is convenient to use a diol, to form a cyclic acetal
(the reaction goes even more readily)
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19.11 Nucleophilic Addition of Phosphorus
Ylides: The Wittig Reaction
 The sequence converts C=O is 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
 Formation of the ylide is shown below
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Mechanism of the Wittig
Reaction
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Uses of the Wittig Reaction
 Can be used for monosubstituted, disubstituted, and
trisubstituted alkenes but not tetrasubstituted alkenes
The reaction yields a pure alkene of known structure
 For comparison, addition of CH3MgBr to
cyclohexanone and dehydration with, yields a mixture
of two alkenes
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19.12 The Cannizaro Reaction
 The adduct of an aldehyde and OH can transfer
hydride ion to another aldehyde C=O resulting in a
simultaneous oxidation and reduction
(disproportionation)
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19.13 Conjugate Nucleophilic Addition to
-Unsaturated Aldehydes and Ketones
 A nucleophile
can add to the
C=C double
bond of an ,unsaturated
aldehyde or
ketone
(conjugate
addition, or 1,4
addition)
 The initial
product is a
resonancestabilized enolate
ion, which is then
protonated
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Conjugate Addition of Amines
 Primary and secondary amines add to , -
unsaturated aldehydes and ketones to yield -amino
aldehydes and ketones
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Conjugate Addition of Alkyl Groups:
Organocopper Reactions
 Reaction of an , -unsaturated ketone with a lithium
diorganocopper reagent
 Diorganocopper (Gilman) reagents form by reaction
of 1 equivalent of cuprous iodide and 2 equivalents of
organolithium
 1, 2, 3 alkyl, aryl and alkenyl groups react but not
alkynyl groups
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Mechanism of Alkyl Conjugate
Addition
 Conjugate nucleophilic addition of a diorganocopper
anion, R2Cu, to an enone
 Transfer of an R group and elimination of a neutral
organocopper species, RCu
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19.14 Spectroscopy of Aldehydes
and Ketones
 Infrared Spectroscopy
 Aldehydes and ketones show a strong C=O peak
1660 to 1770 cm1
 aldehydes show two characteristic C–H absorptions
in the 2720 to 2820 cm1 range.
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C=O Peak Position in the IR
Spectrum
 The precise position of the peak reveals the
exact nature of the carbonyl group
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NMR Spectra of Aldehydes
 Aldehyde proton signals are at  10 in 1H NMR -
distinctive spin–spin coupling with protons on the
neighboring carbon, J  3 Hz
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13C
NMR of C=O
 C=O signal is at  190 to  215
 No other kinds of carbons absorb in this range
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Mass Spectrometry – McLafferty
Rearrangement
 Aliphatic aldehydes and ketones that have hydrogens
on their gamma () carbon atoms rearrange as shown
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Mass Spectroscopy:
-Cleavage
 Cleavage of the bond between the carbonyl group
and the  carbon
 Yields a neutral radical and an oxygen-containing
cation
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