Transcript Chapter 19. Aldehydes and Ketones: Nucleophilic Addition

Chapter 19. Aldehydes and
Ketones: Nucleophilic
Addition Reactions
Based on McMurry’s Organic Chemistry, 6th
edition
©2003 Ronald Kluger
Department of Chemistry
University of Toronto
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
1
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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
2
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 See Table 19.1 for common names
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
3
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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
4
Ketones with Common Names
 IUPAC retains well-used but unsystematic names for
a few ketones
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
5
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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
6
19.2 Preparation of Aldehydes and
Ketones
 Preparing Aldehydes
 Oxidize primary alcohols using pyridinium
chlorochromate
 Reduce an ester with diisobutylaluminum
hydride (DIBAH)
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
7
Preparing Ketones
 Oxidize a 2° alcohol (see Section 17.8)
 Many reagents possible: choose for the specific
situation (scale, cost, and acid/base sensitivity)
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
8
Ketones from Ozonolysis
 Ozonolysis of alkenes yields ketones if one of the
unsaturated carbon atoms is disubstituted (see
Section 7.8)
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
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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)
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
10
Methyl Ketones by Hydrating Alkynes
 Hydration of terminal alkynes in the presence of Hg2+
(catalyst: Section 8.5)
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
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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)
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
12
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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
13
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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
14
19.4 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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
15
Nucleophiles
 Nucleophiles can be negatively charged ( : Nu) or
neutral ( : Nu) at the reaction site
 The overall charge on the nucleophilic species is not
considered
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
16
19.5 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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
17
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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
18
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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
19
19.6 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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
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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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
21
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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
22
Acid-Catalyzed Addition of Water
 Protonation of C=O makes it
more electrophilic
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
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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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
24
19.7 Nucleophilic Addition of HCN:
Cyanohydrin Formation
 Aldehydes and unhindered ketones react with HCN
to yield cyanohydrins, RCH(OH)CN
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
25
Mechanism of Formation of
Cyanohydrins
 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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
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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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
27
19.8 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 +.
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
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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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
29
Hydride Addition
 Convert C=O to CH-OH
 LiAlH4 and NaBH4 react as donors of hydride ion
 Protonation after addition yields the alcohol
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
30
19.9 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)
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
31
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
Note that overall reaction is substitution of RN for O
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
32
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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
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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
+ H3O+
C
C
H
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
R
N
H2 O
C
H
R
R R
R R
C H
H
C
H
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19.10 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
See Figure 19.11 for
a mechanism
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
35
19.11 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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
36
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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
37
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)
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
38
19.12 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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
39
A Note on the Word “Betaines”
 The term “betaines” is an extension from a specific substance (betaine)
that has permanent + and – charges (as in a zwitterion) that cannot be
neutralized by proton transfers (as in normal amino acids). Webster's
Revised Unabridged Dictionary lists: Betaine \Be"ta*ine\, n. [From beta,
generic name of the beet.] (Chem.) A nitrogenous base, {C5H11NO2},
produced artificially, and also occurring naturally in beet-root molasses
and its residues. The listed pronunciation indicates it has the exact
same emphasis as “cocaine”.
 Cocaine \Co"ca*ine\, n. (Chem.) A powerful alkaloid, {C17H21NO4},
obtained from the leaves of coca
 So – if you say “co-ca-een” (as this dictionary suggests) then you would
also say “bee-ta-een”. If you sat “co-cayn” then say “beet-ayn”.
 Whatever you say, the “beta” in “betaine” refers to beets and not a letter
in the Greek alphabet. There have been a lot of wagers on this over the
years.
RK
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
40
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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
41
Mechanism of the Wittig Reaction
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
42
19.13 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)
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
43
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.
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
44
19.14 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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
45
Conjugate Addition of Amines
 Primary and secondary amines add to , b-
unsaturated aldehydes and ketones to yield b-amino
aldehydes and ketones
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
46
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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
47
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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
48
19.15 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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
49
19.16 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.
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
50
C=O Peak Position in the IR Spectrum
 The precise position of the peak reveals the
exact nature of the carbonyl group
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
51
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
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
52
Protons on Carbons Adjacent to C=O
 Slightly deshielded and normally absorb near  2.0 to
2.3
 Methyl ketones always show a sharp three-proton
singlet near  2.1
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
53
13C
NMR of C=O
 C=O signal is at  190 to  215
 No other kinds of carbons absorb in this range
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
54
Mass Spectrometry – McLafferty
Rearrangement
 Aliphatic aldehydes and ketones that have hydrogens
on their gamma () carbon atoms rearrange as shown
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
55
Mass Spectroscopy: -Cleavage
 Cleavage of the bond between the carbonyl group
and the  carbon
 Yields a neutral radical and an oxygen-containing
cation
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
56
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 titaniumcontaining catalyst, gives 97% of the S product and only 3% of
the R
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
57
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)
Based on McMurry, Organic Chemistry, Chapter
19, 6th edition, (c) 2003
58