Transcript Chapter 19. Aldehydes and Ketones: Nucleophilic Addition

Chapter 19. Aldehydes and Ketones:
Nucleophilic Addition Reactions
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Aldehydes and Ketones
• Aldehydes and ketones are characterized by the
the carbonyl functional group (C=O)
• The compounds occur widely in nature as
intermediates in metabolism and biosynthesis
• They are also common as chemicals, as
solvents, monomers, adhesives, agrichemicals
and pharmaceuticals
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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 See Table 19.1 for common names
O
ethanal
O
propanal
O
2-ethyl-4-methylpentanal
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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
O
3-hexanone
O
4-hexen-2-one
O
O
2,4-hexandione
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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 is
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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Preparation of Aldehydes and Ketones
• Preparing Aldehydes
• Oxidize primary alcohols using pyridinium chlorochromate
• Reduce an ester with diisobutylaluminum hydride (DIBAH)
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Preparing Ketones
• Oxidize a 2° alcohol (see Section 17.8)
• 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
(see Section 7.8)
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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
(see Section 16.4)
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Methyl Ketones by Hydrating Alkynes
• Hydration of terminal alkynes in the presence of
Hg2+ (catalyst: Section 8.5)
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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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Nucleophilic Addition Reactions of Aldehydes
and Ketones
• Nu- approaches 45° 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
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Other Nucleophiles
• 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 electrophilic than the
carbonyl group of an aliphatic aldehyde
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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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Relative Energies
• Equilibrium generally favors the carbonyl
compound over hydrate for steric reasons
– Acetone in water is 99.9% ketone form
• Exception: simple aldehydes
– In water, formaldehyde consists is 99.9% hydrate
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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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Nucleophilic Addition of HCN:
Cyanohydrin Formation
• Aldehydes and unhindered ketones react with
HCN to yield cyanohydrins, RCH(OH)CN
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Mechanism of Formation of
Cyanohydrins
• Addition of HCN is reversible and basecatalyzed, 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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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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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)
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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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Note that overall reaction is substitution of RN for O
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
2,4-dinitrophenylhydrazine 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
R R
O
O
C
H
+ R2NH
H
C
NH
HO
H+
N
C
C
N
H
H
C
H
R
N
H2 O
C
+ H3O+
C
C
H
R
R R
R R
C H
H
C
H
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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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Nucleophilic Addition of Alcohols: Acetal
Formation
• Two equivalents of ROH in the presence of an
acid catalyst add to C=O to yield acetals,
R2C(OR)2
• These can be called ketals if derived from a
ketone
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Formation of Acetals
• 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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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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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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Mechanism of the Wittig
Reaction
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The Cannizzaro Reaction:
Biological Reductions
• 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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The Biological Analogue of the
Canizzaro Reaction
• Enzymes catalyze the reduction of aldehydes and
ketones using NADH as the source of the equivalent of
H• The transfer resembles that in the Cannizzaro reaction
but the carbonyl of the acceptor is polarized by an acid
from the enzyme, lowering the barrier
Enzymes are chiral
and the reactions are
stereospecific. The
stereochemistry
depends on the
particular enzyme
involved.
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Conjugate Nucleophilic Addition to ,bUnsaturated Aldehydes and Ketones
• A nucleophile
can add to the
C=C double
bond of an ,bunsaturated
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 , bunsaturated aldehydes and ketones to yield bamino aldehydes and ketones
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Conjugate Addition of Alkyl Groups:
Organocopper Reactions
• Reaction of an , b-unsaturated ketone with a lithium
diorganocopper reagent
• Diorganocopper (Gilman) reagents from 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, an enone
• Transfer of an R group and elimination of a neutral
organocopper species, RCu
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Biological Nucleophilic Addition
Reactions
• Example: Many enzyme reactions involve pyridoxal phosphate
(PLP), a derivative of vitamin B6, as a co-catalyst
• PLP is an aldehyde that readily forms imines from amino
groups of substrates, such as amino acids
• The imine undergoes a proton shift that leads to the net
conversion of the amino group of the substrate into a carbonyl
group
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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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Protons on Carbons Adjacent to
C=O
• Slightly deshielded and normally absorb near 
2.0 to 2.3
• Methyl ketones always show a sharp threeproton singlet near  2.1
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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 oxygencontaining cation
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Enantioselective Synthesis
• When a chiral product is formed achiral reagents, we get
both enantiomers in equal amounts - the transition
states are mirror images and are equal in energy
• However, if the reaction is subject to catalysis, a chiral
catalyst can create a lower energy pathway for one
enantiomer - called an enantionselective synthesis
• Reaction of benzaldehyde with diethylzinc with a chiral
titanium-containing catalyst, gives 97% of the S product
and only 3% of the R
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Summary
• Aldehydes are from oxidative cleavage of alkenes, oxidation of 1°
alcohols, or partial reduction of esters
• Ketones are from oxidative cleavage of alkenes, oxidation of 2°
alcohols, or by addition of diorganocopper reagents to acid
chlorides.
• Aldehydes and ketones are reduced to yield 1° and 2° alcohols ,
respectively
• Grignard reagents also gives alcohols
• Addition of HCN yields cyanohydrins
• 1° amines add to form imines, and 2° amines yield enamines
• Reaction of an aldehyde or ketone with hydrazine and base yields
an alkane
• Alcohols add to yield acetals
• Phosphoranes add to aldehydes and ketones to give alkenes (the
Wittig reaction)
• b-Unsaturated aldehydes and ketones are subject to conjugate
addition (1,4 addition)
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