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Chapter 19. Aldehydes and Ketones: Nucleophilic Addition Reactions

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Chapter 19. Aldehydes and Ketones: Nucleophilic Addition Reactions Aldehydes and Ketones Aldehydes and ketones are characterized by the the carbonyl functional group ... – PowerPoint PPT presentation

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Title: Chapter 19. Aldehydes and Ketones: Nucleophilic Addition Reactions


1
Chapter 19. Aldehydes and Ketones Nucleophilic
Addition Reactions
2
Aldehydes and Ketones
  • Aldehydes and ketones are characterized by the
    the carbonyl functional group (CO)
  • 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

3
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

4
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

5
Ketones with Common Names
  • IUPAC retains well-used but unsystematic names
    for a few ketones

6
Ketones and Aldehydes as Substituents
  • The RCO 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

7
Preparation of Aldehydes and Ketones
  • Preparing Aldehydes
  • Oxidize primary alcohols using pyridinium
    chlorochromate
  • Reduce an ester with diisobutylaluminum hydride
    (DIBAH)

8
Preparing Ketones
  • Oxidize a 2 alcohol (see Section 17.8)
  • Many reagents possible choose for the specific
    situation (scale, cost, and acid/base sensitivity)

9
Ketones from Ozonolysis
  • Ozonolysis of alkenes yields ketones if one of
    the unsaturated carbon atoms is disubstituted
    (see Section 7.8)

10
Aryl Ketones by Acylation
  • FriedelCrafts acylation of an aromatic ring with
    an acid chloride in the presence of AlCl3
    catalyst (see Section 16.4)

11
Methyl Ketones by Hydrating Alkynes
  • Hydration of terminal alkynes in the presence of
    Hg2 (catalyst Section 8.5)

12
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)

13
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

14
Ketones Oxidize with Difficulty
  • Undergo slow cleavage with hot, alkaline KMnO4
  • CC bond next to CO is broken to give carboxylic
    acids
  • Reaction is practical for cleaving symmetrical
    ketones

15
Nucleophilic Addition Reactions of Aldehydes and
Ketones
  • Nu- approaches 45 to the plane of CO and adds
    to C
  • A tetrahedral alkoxide ion intermediate is
    produced

16
Nucleophiles
  • Nucleophiles can be negatively charged ( Nu?)
    or neutral ( Nu) at the reaction site

17
Other Nucleophiles
  • The overall charge on the nucleophilic species is
    not considered

18
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 CO ketones have two

19
Electrophilicity of Aldehydes and Ketones
  • Aldehyde CO is more polarized than ketone CO
  • As in carbocations, more alkyl groups stabilize
    character
  • Ketone has more alkyl groups, stabilizing the CO
    carbon inductively

20
Reactivity of Aromatic Aldehydes
  • Less reactive in nucleophilic addition reactions
    than aliphatic aldehydes
  • Electron-donating resonance effect of aromatic
    ring makes CO less reactive electrophilic than
    the carbonyl group of an aliphatic aldehyde

21
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

22
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

23
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

24
Acid-Catalyzed Addition of Water
  • Protonation of CO makes it more electrophilic

25
Addition of H-Y to CO
  • Reaction of CO with H-Y, where Y is
    electronegative, gives an addition product
    (adduct)
  • Formation is readily reversible

26
Nucleophilic Addition of HCN Cyanohydrin
Formation
  • Aldehydes and unhindered ketones react with HCN
    to yield cyanohydrins, RCH(OH)C?N

27
Mechanism of Formation of Cyanohydrins
  • Addition of HCN is reversible and base-catalyzed,
    generating nucleophilic cyanide ion, CN
  • Addition of CN? to CO yields a tetrahedral
    intermediate, which is then protonated
  • Equilibrium favors adduct

28
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

29
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 carbonmagnesium
    bond is strongly polarized, so a Grignard reagent
    reacts for all practical purposes as R ? MgX .

30
Mechanism of Addition of Grignard Reagents
  • Complexation of CO 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

31
Hydride Addition
  • Convert CO to CH-OH
  • LiAlH4 and NaBH4 react as donors of hydride ion
  • Protonation after addition yields the alcohol

32
Nucleophilic Addition of Amines Imine and
Enamine Formation
  • RNH2 adds to CO to form imines, R2CNR (after
    loss of HOH)
  • R2NH yields enamines, R2N?CRCR2 (after loss of
    HOH)
  • (ene amine unsaturated amine)

33
Mechanism of Formation of Imines
  • Primary amine adds to CO
  • 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
34
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
    2,4-dinitrophenylhydrazones
  • These are usually solids and help in
    characterizing liquid ketones or aldehydes by
    melting points

35
Enamine Formation
  • After addition of R2NH, proton is lost from
    adjacent carbon

36
Nucleophilic Addition of Hydrazine The
WolffKishner 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

37
Nucleophilic Addition of Alcohols Acetal
Formation
  • Two equivalents of ROH in the presence of an acid
    catalyst add to CO to yield acetals, R2C(OR?)2
  • These can be called ketals if derived from a
    ketone

38
Formation of Acetals
  • Alcohols are weak nucleophiles but acid promotes
    addition forming the conjugate acid of CO
  • 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, R2COR to which a second alcohol
    adds to form the acetal

39
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)

40
Nucleophilic Addition of Phosphorus Ylides The
Wittig Reaction
  • The sequence converts CO is to CC
  • 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)3PO
  • Formation of the ylide is shown below

41
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

42
Mechanism of the Wittig Reaction
43
The Cannizzaro Reaction Biological Reductions
  • The adduct of an aldehyde and OH? can transfer
    hydride ion to another aldehyde CO resulting in
    a simultaneous oxidation and reduction
    (disproportionation)

44
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.
45
Conjugate Nucleophilic Addition to
?,b-Unsaturated Aldehydes and Ketones
  • A nucleophile can add to the CC double bond of
    an ?,b-unsaturated aldehyde or ketone (conjugate
    addition, or 1,4 addition)
  • The initial product is a resonance-stabilized
    enolate ion, which is then protonated

46
Conjugate Addition of Amines
  • Primary and secondary amines add to ?,
    b-unsaturated aldehydes and ketones to yield
    b-amino aldehydes and ketones

47
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

48
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

49
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

50
Spectroscopy of Aldehydes and Ketones
  • Infrared Spectroscopy
  • Aldehydes and ketones show a strong CO peak 1660
    to 1770 cm?1
  • aldehydes show two characteristic CH absorptions
    in the 2720 to 2820 cm?1 range.

51
CO Peak Position in the IR Spectrum
  • The precise position of the peak reveals the
    exact nature of the carbonyl group

52
NMR Spectra of Aldehydes
  • Aldehyde proton signals are at ? 10 in 1H NMR -
    distinctive spinspin coupling with protons on
    the neighboring carbon, J ? 3 Hz

53
Protons on Carbons Adjacent to CO
  • Slightly deshielded and normally absorb near ?
    2.0 to ?2.3
  • Methyl ketones always show a sharp three-proton
    singlet near ? 2.1

54
13C NMR of CO
  • CO signal is at ? 190 to ? 215
  • No other kinds of carbons absorb in this range

55
Mass Spectrometry McLafferty Rearrangement
  • Aliphatic aldehydes and ketones that have
    hydrogens on their gamma (?) carbon atoms
    rearrange as shown

56
Mass Spectroscopy ?-Cleavage
  • Cleavage of the bond between the carbonyl group
    and the ? carbon
  • Yields a neutral radical and an oxygen-containing
    cation

57
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

58
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)
  • ??-Unsaturated aldehydes and ketones are subject
    to conjugate addition (1,4 addition)
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