Substitution Reactions of Carbonyl Compounds at the Carbon

1
Chapter 23
Substitution Reactions of Carbonyl Compounds at
the ? Carbon
2
Enols

• Enol and keto forms are tautomers of the carbonyl
  group that differ in the position of the double
  bond and a proton.
• These constitutional isomers are in equilibrium
  with each other.

3
Enols

• The CO bond is much stronger than a CC bond, so
  equilibrium favors the keto form for most
  carbonyl compounds.
• Rule of thumb, lt 1 of the enol is present at
  equilibrium.
• With unsymmetrical ketones, two different enols
  are possible, still at only about lt 1.

4
Enols

• With compounds containing two carbonyl groups
  separated by a single carbon (called ?-dicarbonyl
  or 1,3-dicarbonyl compounds), the concentration
  of the enol form can be greater than the
  concentration of the keto form.

• Conjugation and intramolecular hydrogen bonding
  help stabilize the enol. H-bonding especially
  important when a six-membered ring is formed.

5
Enols

• Tautomerization is catalyzed by both acid and
  base.

6
Enols are electron rich and so they react with
nucleophiles

• Enols are more electron rich than alkenes because
  the OH group has a electron-donating resonance
  effect.
• The nucleophilic carbon can react with an
  electrophile to form a new bond to carbon.

7
Enolates

• Enolates are formed when a base removes a proton
  on a carbon that is ? to a carbonyl group.
• The CH bond on the ? carbon is more acidic than
  many other sp3 hybridized CH bonds, because the
  resulting enolate is resonance stabilized.

8
Enolates

• The pKa of the ? hydrogen in an aldehyde or a
  ketone is 20. This makes it much more acidic
  than the CH bonds in alkanes and alkenes, but
  still less acidic than OH bonds in alcohols or
  carboxylic acids.

9
Enolates
10
Enolates of esters and nitriles

• Enolates can be formed from esters and 3 amides
  too, but the ? hydrogens from these compounds are
  less acidic.
• Nitriles also have acidic protons on the carbon
  adjacent to the cyano group.

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Enolates

• The protons on the carbon between the two
  carbonyl groups of a ?-dicarbonyl compound are
  especially acidic because resonance delocalizes
  the negative charge on two different oxygen atoms.

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Enolates pKa
13
Enolates

• The formation of an enolate is an acid-base
  equilibrium, so the stronger the base, the more
  enolate that forms.

• The extent of an acid-base reaction can be
  predicted by comparing the pKa of the starting
  acid with the pKa of the conjugate acid formed.
  The equilibrium favors the side with the weaker
  acid.
• Common bases used to form enolates are OH, OR,
  H and dialkylamides (NR2).

14
Enolates
15
Enolate formation

• Strong non-nucleoplilic bases such as lithium
  diisopropylamide, LiNCH(CH3)22, LDA, are
  very good at forming enolates.

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Enolate formation

• LDA quickly deprotonates essentially all of the
  carbonyl starting material, even at 78C, to
  form the enolate product. THF is the typical
  solvent for these reactions.

• LDA can be prepared by deprotonating
  diisopropylamine with an organolithium reagent
  such as butyllithium, and then used immediately
  in a reaction.

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Enolates

• Enolates are nucleophiles that react with a
  variety of electrophiles.
• Enolates are resonance stabilized, so they have
  two reactive sitesthe carbon and oxygen atoms
  that bear the negative charge (O alkylation vs
  C alkylation).
• A nucleophile with two reaction sites is called
  an ambident nucleophile.
• In theory, each of these atoms could react with
  an electrophile to form two different products,
  one with a new bond to carbon, and one with a new
  bond to oxygen.

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Enolates

• An enolate usually reacts at the carbon end,
  because this site is more nucleophilic.

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Enolates of Unsymmetrical Carbonyl
Compounds kinetic vs theromodynamic enolates

• When an unsymmetrical carbonyl compound like
  2-methylcyclohexanone is treated with base, two
  enolates are possible.

• Path 1 occurs faster because it results in
  removal of the less hindered 2 H. Path 2
  results in formation of the more stable enolate.
  This enolate predominates at equilibrium.

20
Enolates of Unsymmetrical Carbonyl Compounds

• Depending on reaction conditions used (base,
  solvent and reaction temperature) , you can
  regioselectively form one or the other enolate.
• The kinetic enolate forms faster, so mild
  reaction conditions favor it over slower
  processes with higher energies of activation.
• The kinetic enolate is the less stable enolate,
  so it should not be allowed to equilibrate to the
  more stable thermodynamic enolate.

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A kinetic enolate is favored by

• A strong, bulky, nonnucleophilic base (like LDA)
  helps ensure that the enolate is formed
  rapidly, and removes the more accessible proton
  on the less substituted carbon much faster than a
  more hindered proton.
• Polar aprotic solvent (THF) the solvent must be
  polar to dissolve the polar starting materials
  and intermediates. It must be aprotic so that it
  does not protonate any enolate that is formed.
• Low temperaturethe temperature must be low
  (-78C) to prevent the kinetic enolate from
  equilibrating to the thermodynamic enolate.

22
A thermodynamic enolate is favored by

• A strong baseA strong base yields both enolates,
  but in a protic solvent (see below), enolates can
  also be protonated to re-form the carbonyl
  starting material. At equilibrium, the lower
  energy intermediate always wins out so that the
  more stable, more substituted enolate is present
  in a higher concentration. Common bases are
  NaOCH2CH3, KOC(CH3)3, or other alkoxides.
• A protic solvent (CH3CH2OH or other alcohols).
• Room temperature (25C).

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Racemization at the ? Carbon Watch Out !

• Enolates are stabilized by the delocalization.
• The electron pair on the carbon adjacent to the
  CO must occupy a p orbital that overlaps with
  the two other p orbitals of the CO, making an
  enolate conjugated.
• All three atoms of the enolate are sp2 hybridized
  and trigonal planar.

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Reactions of EnolatesHalogenation at the ? Carbon

• Treatment of a ketone or aldehyde with halogen
  and either acid or base results in substitution
  of X for H on the ? carbon, forming an ?-halo
  aldehyde or ketone.

• Reactions performed in acid involve enol
  intermediates.
• Reactions in base involve enolate intermediates.

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Reactions of EnolatesHalogenation at the ? Carbon

• When halogenation is conducted in the presence of
  acid, the acid often used is acetic acid, which
  serves as both the solvent and the acid catalyst
  for the reaction.

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Reactions of EnolatesHalogenation at the ? Carbon
27
Reactions of EnolatesHalogenation at the ? Carbon

• Halogenation in base is much less useful, because
  it is often difficult to stop the reaction after
  addition of just one halogen atom to the ?
  carbon.
• Can you suggest why?

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Reactions of EnolatesHalogenation at the ? Carbon
29
Reactions of EnolatesHalogenation at the ? Carbon

• It is difficult to stop the reaction after the
  addition of one Br atom because the
  electron-withdrawing inductive effect of Br
  stabilizes the second enolate.
• Halogenation of a methyl ketone with excess
  halogen, haloform reaction, results in the
  cleavage of a CC ? bond and formation of two
  products, a carboxylate anion and CHX3 (commonly
  called haloform).

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Reactions of EnolatesHalogenation at the ? Carbon

• In the haloform reaction, the three H atoms of
  the CH3 group are successively replaced by X to
  form an intermediate that is oxidatively cleaved
  with base.
• Methyl ketones form iodoform (CHI3), a pale
  yellow solid that precipitates from the reaction
  mixture. This reaction is the basis of the
  iodoform test to detect methyl ketones. Methyl
  ketones give a positive iodoform test (appearance
  of a yellow solid) whereas other ketones give a
  negative iodoform test (no change in the reaction
  mixture).

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Reactions of EnolatesHalogenation at the ? Carbon
32
Reactions of ?-Halo Carbonyl Compounds

• ?-Halo carbonyl compounds undergo two useful
  reactionselimination with base and substitution
  with nucleophiles.
• By a two step method involving elimination, a
  carbonyl compound such as cyclohexanone can be
  converted into an ?,?unsaturated carbonyl
  compound.

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Reactions of ?-Halo Carbonyl Compounds

• ?-Halo carbonyl compounds also react with
  nucleophiles by SN2 reactions. For example,
  reaction of 2-bromocyclo- hexanone with CH3NH2
  produces the substitution product.

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Reactions of ?-Halo Carbonyl Compounds

• Example An intramolecular nucleophilic
  substitution of an ?-halo ketone was used in the
  synthesis of the antimalarial drug quinine.

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Reactions of EnolatesDirect Enolate Alkylation

• Treatment of an aldehyde or ketone with base and
  an alkyl halide results in alkylationthe
  substitution of R for H on the ? carbon atom.

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Reactions of EnolatesDirect Enolate Alkylation

• The second step is an SN2 reaction, so it only
  works well with unhindered methyl and 1 alkyl
  halides. Hindered alkyl halides and those with
  halogens bonded to sp2 hybridized carbons do not
  undergo substitution.

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Reactions of EnolatesDirect Enolate Alkylation

• The stereochemistry of enolate alkylation follows
  the general rule governing stereochemistry of
  reactions an achiral starting material yields an
  achiral or racemic product.

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Reactions of EnolatesDirect Enolate Alkylation

• An unsymmetrical ketone can be regioselectively
  alkylated to yield one major product.
• Treatment of 2-methylcyclohexanone with LDA in
  THF solution at 78C gives the less substituted
  kinetic enolate, which then reacts with CH3I to
  form A.

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Reactions of EnolatesDirect Enolate Alkylation

• Example Treatment of 2-methylcyclohexanone with
  NaOCH2CH3 in CH3CH2OH solution at room
  temperature forms the more substituted
  thermodynamic enolate, which then reacts with
  CH3I to form B.

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Reactions of EnolatesApplications of Enolate
Alkylations

• Example In the synthesis of tamoxifen, a potent
  anticancer drug, enolate formation and alkylation
  with CH3CH2I is used.

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Reactions of EnolatesMalonic Ester Synthesis

• The malonic ester synthesis results in the
  preparation of carboxylic acids having general
  structures

• The malonic ester synthesis is a stepwise method
  for converting diethyl malonate into a carboxylic
  acid having one or two alkyl groups on the ?
  carbon.

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Reactions of EnolatesMalonic Ester Synthesis

• Heating diethyl malonate with acid and water
  hydrolyzes both esters to carboxy groups, forming
  a ?-diacid (1,3-diacid).

• ?-Diacids are unstable to heat and decarboxylate
  resulting in cleavage of a CC bond and formation
  of a carboxylic acid.

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Reactions of EnolatesMalonic Ester Synthesis

• The net result of decarboxylation is cleavage of
  a CC bond on the ? carbon, with loss of CO2.

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Reactions of EnolatesMalonic Ester Synthesis

• Thus, the malonic ester synthesis converts
  diethyl malonate to a carboxylic acid in three
  steps.

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Reactions of EnolatesMalonic Ester Synthesis

• Example The synthesis of 2-butanoic acid
  (CH3CH2CH2COOH) from diethyl malonate

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Reactions of EnolatesMalonic Ester Synthesis

• If the first two steps of the reaction sequence
  are repeated prior to hydrolysis and
  decarboxylation, then a carboxylic acid having
  two new alkyl groups on the ? carbon can be
  synthesized.

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Reactions of EnolatesMalonic Ester Synthesis

• An intramolecular malonic ester synthesis can be
  used to form rings having three to six atoms, if
  the appropriate dihalide is used as starting
  material.

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Reactions of EnolatesMalonic Ester Synthesis

• To use the malonic ester synthesis, you must be
  able to determine what starting materials are
  needed to prepare a given compound.

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Reactions of EnolatesAcetoacetic Ester Synthesis

• The acetoacetic ester synthesis results in the
  preparation of methyl ketones having general
  structures

• The acetoacetic ester synthesis is a stepwise
  method for converting ethyl acetoacetate into a
  ketone having one or two alkyl groups on the ?
  carbon.

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Reactions of EnolatesAcetoacetic Ester Synthesis

• The steps in acetoacetic ester synthesis are the
  same as those in the malonic ester synthesis.
  Because the starting material is a ?-ketoester,
  the final product is a ketone, not a carboxylic
  acid.

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Reactions of EnolatesAcetoacetic Ester Synthesis

• If the first two steps of the reaction sequence
  are repeated before hydrolysis and
  decarboxylation, then a ketone having two new
  alkyl groups on the ? carbon can be synthesized.

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Reactions of EnolatesAcetoacetic Ester Synthesis

• To determine what starting materials are needed
  to prepare a given ketone using the acetoacetic
  ester synthesis

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Reactions of EnolatesAcetoacetic Ester Synthesis

• The acetoacetic ester synthesis and direct
  enolate alkylation are two different methods that
  can prepare similar ketones.

• Direct enolate alkylation requires a very strong
  base like LDA to be successful.
• Acetoacetic ester synthesis utilizes NaOEt, which
  is prepared from cheaper starting materials.
• Each method has its own advantages and
  disadvantages. (can you suggest a few?)