Chapter 19. Aldehydes and Ketones: Nucleophilic Addition Reactions

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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 (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

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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

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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

5
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 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

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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

• FriedelCrafts 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
• CC bond next to CO 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 CO 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 CO ketones have two

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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

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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 CO 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 CO makes it more electrophilic

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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

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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 base-catalyzed,
  generating nucleophilic cyanide ion, CN
• Addition of CN? to CO 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 carbonmagnesium
  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 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

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Hydride Addition

• Convert CO 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 CO to form imines, R2CNR (after
  loss of HOH)
• R2NH yields enamines, R2N?CRCR2 (after loss of
  HOH)
• (ene amine unsaturated amine)

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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
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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
  2,4-dinitrophenylhydrazine readily forms
  2,4-dinitrophenylhydrazones
• 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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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

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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

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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

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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 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

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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 CO 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
?,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

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Conjugate Addition of Amines

• Primary and secondary amines add to ?,
  b-unsaturated aldehydes and ketones to yield
  b-amino 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 CO peak 1660
  to 1770 cm?1
• aldehydes show two characteristic CH absorptions
  in the 2720 to 2820 cm?1 range.

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CO 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 spinspin coupling with protons on
  the neighboring carbon, J ? 3 Hz

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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

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13C NMR of CO

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