Aldehydes from oxidation of primary alcohols using the Dess-Martin periodinane reagent

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14.2 Preparing Aldehydes and Ketones

• Aldehydes from oxidation of primary alcohols
  using the Dess-Martin periodinane reagent

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Preparing Aldehydes and Ketones

• Aldehydes from reduction of carboxylic esters
  using diisobutylaluminum hydride (DIBAH)

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Preparing Aldehydes and Ketones

• Secondary alcohols are oxidized by variety of
  chromium-based reagents to give ketones
• Aryl ketones from Friedel-Crafts acylation
  reactions

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Nucleophilic Addition of Grignard and Hydride
Reagents Alcohol Formation

• Mechanism of Grignard Reaction

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Nucleophilic Addition of Grignard and Hydride
Reagents Alcohol Formation

• In an analogous manner the reaction of aldehydes
  and ketones with hydride reagents may be
  represented as proceeding through a nucleophilic
  addition of a hydride ion (H) to the CO carbon
• LiAlH4 and NaBH4 act as if they are donors of
  hydride ion

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14.7 Nucleophilic Addition of Amines Imine and
Enamine Formation

• Primary amines, RNH2, add to aldehydes and
  ketones to yield imines, R2CNR
• Secondary amines, R2NH, add similarly to yield
  enamines, R2N-CRCR2

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Nucleophilic Addition of Amines Imine and
Enamine Formation

• Imines are common biological intermediates where
  they are often called Schiff bases

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Nucleophilic Addition of Amines Imine and
Enamine Formation

• Imine and enamine formations reach maximum rate
  around pH 4 to 5
• Slow at pH gt 5 because there is insufficient H
  present in solution to protonate intermediate
  carbinolamine OH to yield the better leaving
  group OH2
• Slow at pH lt 4 because the basic amine
  nucleophile is protonated and initial
  nucleophilic addition cannot occur

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Worked Example 14.1Predicting the Product of
Reaction between a Ketone and an Amine
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Nucleophilic Addition of Alcohols Acetal
Formation

• Acetal and hemiacetal groups are common in
  carbohydrate chemistry
• Glucose, a polyhydroxy aldehyde, undergoes
  intramolecular nucleophilic addition
• Exists primarily as a cyclic hemiacetal

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14.9 Nucleophilic Addition of Phosphorus Ylides
The Wittig Reaction

• Wittig reaction
• Converts aldehydes and ketones into alkenes
• Phosphorus ylide, R2CP(C6H5)3, adds to aldehyde
  or ketone to yield dipolar, alkoxide ion
  intermediate
• Ylide (pronounced ill-id) is a neutral, dipolar
  compound with adjacent positive and negative
  charges
• Also called a phosphorane and written in the
  resonance form R2CP(C6H5)3
• Dipolar intermediate spontaneously decomposes
  through a four-membered ring to yield alkene and
  triphenylphosphine oxide, (Ph)3PO
• Wittig reaction results in replacement of
  carbonyl oxygen with R2C group of original
  phosphorane

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Nucleophilic Addition of Phosphorus Ylides The
Wittig Reaction
Wittig reaction mechanism
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Nucleophilic Addition of Phosphorus Ylides The
Wittig Reaction

• Phosphorus ylides are prepared by SN2 reaction of
  primary and some secondary alkyl halides with
  triphenylphosphine, (Ph)3P, followed by treatment
  with base

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Nucleophilic Addition of Phosphorus Ylides The
Wittig Reaction

• Wittig reactions used commercially to synthesize
  numerous pharmaceuticals

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Worked Example 14.3Synthesizing an Alkene
Using a Wittig Reaction

• What carbonyl compound and what phosphorus ylide
  might you use to prepare 3-ethylpent-2-ene?

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Worked Example 14.3Synthesizing an Alkene
Using a Wittig Reaction
Solution
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Biological Reductions

• Cannizzaro reaction is a nucleophilic acyl
  substitution reaction of aldehydes and ketones
• OH adds to aldehyde to give tetrahedral
  intermediate
• H ion is transferred to a second aldehyde
• The aldehyde accepting the H ion is reduced and
  the aldehyde transferring the H is oxidized

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Biological Reductions

• Cannizzaro reaction mechanism is analogous to
  biological reduction in living organisms by
  nicotinamide adenine dinucleotide, NADH
• NADH donates H to aldehydes and ketones,
  similar to tetrahedral alkoxide intermediate in
  Cannizzaro reaction

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Conjugate Nucleophilic Addition to
a,ß-Unsaturated Aldehydes and Ketones

• Conjugate addition occurs because the nucleophile
  can add to either one of two electrophilic
  carbons of the a,b-unsaturated aldehyde or ketone

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Conjugate Nucleophilic Addition to
a,ß-Unsaturated Aldehydes and Ketones

• Conjugated double bond of a,b-unsaturated
  carbonyl is activated by carbonyl group of the
  aldehyde or ketone
• CC double bond is not activated for addition in
  absence of carbonyl group

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Conjugate Nucleophilic Addition to
a,ß-Unsaturated Aldehydes and Ketones

• Primary and secondary amines add to
  a,b-unsaturated aldehydes and ketones to yield
  b-amino aldehydes and ketones
• Both 1,2- and 1,4-addition occur
• Additions are reversible
• More stable conjugate addition product
  accumulates

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Conjugate Nucleophilic Addition to
a,ß-Unsaturated Aldehydes and Ketones

• Conjugate addition of an alkyl or other organic
  group to an a,b-unsaturated ketone (but not
  aldehyde) is a useful 1,4-addition reaction

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Conjugate Nucleophilic Addition to
a,ß-Unsaturated Aldehydes and Ketones

• Conjugate addition of alkyl groups to an
  a,b-unsaturated ketone (not aldehyde) is
  accomplished with a lithium diorganocopper
  reagent, R2CuLi (Gilman reagent)
• Lithium diorganocopper reagent is prepared by
  reaction of 1 equivalent of copper(I) iodide and
  2 equivalents of an organolithium reagent, RLi
• Organolithium reagent is prepared by reaction of
  lithium metal with an organohalide

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Conjugate Nucleophilic Addition to
a,ß-Unsaturated Aldehydes and Ketones

• Primary, secondary, and even tertiary alkyl
  groups undergo conjugate addition
• Alkynyl groups react poorly
• Grignard reagents and organolithium reagents
  normally give direct carbonyl addition to
  a,b-unsaturated ketones

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Worked Example 14.4Using a Conjugate Addition
Reaction

• How might you use a conjugate addition reaction
  to prepare 2-methyl-3-propylcyclopentanone?

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Worked Example 14.4Using a Conjugate Addition
Reaction

• Solution

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Spectroscopy of Aldehydes and Ketones
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Spectroscopy of Aldehydes and Ketones

• Aldehyde protons (RCHO) absorb near 10 d in the
  1H NMR
• Aldehyde proton shows spin-spin coupling with
  protons on the neighboring carbon, with coupling
  constant J 3 Hz
• Hydrogens on carbon next to a carbonyl group are
  slightly deshielded and absorb near to 2.0 to 2.3
  d

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Spectroscopy of Aldehydes and Ketones

• Carbonyl-group carbon atoms of aldehydes and
  ketones have characteristic 13C NMR resonances in
  the range of 190 to 215 d