Carbon-Carbon Bond Formation and Synthesis

1
Carbon-Carbon Bond Formation and Synthesis
2
Organometallic Compounds

• Recall two extremely important reactions of
  metals and organometallic compounds
• Oxidative addition The addition of a reagent to
  a metal center causing it to add two substituents
  which extract two electrons from the metal and
  increasing its oxidation state by two.
• Reductive elimination The elimination of two
  substituents which donate two electrons to the
  metal center causing the oxidation state of the
  metal to decrease by two.

3
Heck Reaction

• Overall A palladium-catalyzed reaction in which
  the R group of RX, a haloalkene or haloarene, is
  substituted for a vinylic H of an alkene.

4
Heck Reaction (consider the alkene)

• Substitution (H ? R) is highly regioselective
  most commonly at the less substituted carbon of
  the double bond.
• Substitution is highly stereoselective the E
  configuration is often formed almost exclusively.

E
Less substituted, H ? Ph substitution occurs here.
Neither E nor Z
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Heck Reaction (RX Haloalkene)

• For RX haloalkene Reaction is stereospecific
  the configuration of the double bond in the
  haloalkene is preserved.

E
E
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Heck Reaction. Some considerations.

• The catalyst
• most commonly Pd(II) acetate.
• reduced in situ to Pd(0).
• reaction of Pd(0) with good ligands gives PdL2.
• The organic halogen compound aryl, heterocyclic,
  benzylic, and vinylic iodides, chlorides,
  bromides, and triflates (CF3SO2O-).
• alkyl halides with an easily eliminated b
  hydrogen are rarely used because they undergo
  b-elimination to give alkenes.
• OH groups and the CO groups of aldehydes,
  ketones, and esters are unreactive under Heck
  conditions.

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Heck Reaction. More

• The alkene
• The less the crowding on the alkene, the more
  reactive it is.
• The base
• Triethylamine, sodium, and potassium acetate, and
  sodium hydrogen carbonate are most common
• The solvent.
• Polar aprotic solvents such as DMF, acetonitrile,
  and DMSO.
• aqueous methanol may also be used.
• The ligand
• Triphenylphosphine, PPh3, is one of the most
  common.

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Heck Reaction
Start here
L PPh3
R
0
II
II
II
II
Rotation about the C-C bond. This is where the R
is swapped in, replacing the H.
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Heck Reaction

• The usual pattern of acyclic compounds
  replacement of a hydrogen of the double bond with
  the R group.
• If the R group has no H for syn elimination, then
  a b H may be abstracted elsewhere.

This b H should be brought into position for syn
elimination with the Pd. Cant happen due to
cyclohexane ring.
10
Suzuki Coupling

• Suzuki coupling A palladium-catalyzed reaction
  of an organoborane (R-BY2) or organoborate
  (RB(OMe)2) with an alkenyl, aryl, or alkynyl
  halide, or triflate (R-X) to yield R-R.

Overall
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Suzuki Coupling

• Recall boranes are easily prepared from alkenes
  or alkynes by hydroboration.
• Borates are prepared from alkyl or aryl lithium
  compounds and trimethylborate.

PhCl Li
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Suzuki Coupling

• These examples illustrate the versatility of the
  reaction.

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Suzuki Coupling
Oxid. Addn
Reductive elimination
Transmetalation R1 and OtBu swap
Substitution
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Alkene Metathesis

• Alkene metathesis A reaction in which two
  alkenes interchange carbons on their double
  bonds.
• If the reaction involves 2,2-disubstituted
  alkenes, ethylene is lost to give a single alkene
  product.

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Alkene Metathesis

• A useful variant of this reaction uses a starting
  material in which both alkenes are in the same
  molecule, and the product is a cycloalkene.
• Catalysts for these reactions are a class of
  compounds called stable nucleophilic carbenes.

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Stable Nucleophilic Carbenes

• Carbenes and carbenoids provide the best route to
  three membered carbon rings.
• Most carbenes are highly reactive electrophiles.
• Carbenes with strongly electron-donating atoms,
  however, for example nitrogen atoms, are
  particularly stable.
• Rather than being electron deficient, these
  carbenes are nucleophiles because of the strong
  electron donation by the nitrogens.
• Because they donate electrons well, they are
  excellent ligands (resembling phosphines) for
  certain transition metals.
• The next screen shows a stable nucleophilic
  carbene.

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Nucleophilic Carbene

• A stable nucleophilic carbene.

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Alkene Metathesis Catalyst

• A useful alkene methathesis catalyst consists of
  ruthenium, Ru, complexed with nucleophilic
  carbenes and another carbenoid ligand.
• In this example, the other carbenoid ligand is a
  benzylidene group.

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Ring-Closing Alkene Metathesis

• Like the Heck reaction, alkene metathesis
  involves a catalytic cycle
• Addition of a metallocarbenoid to the alkene
  gives a four-membered ring.
• Elimination of an alkene in the opposite
  direction gives a new alkene.

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Ring-Closing Alkene Metathesis
21
Ring-Closing Alkene Metathesis
Initiation Step
Cycle
start
22
Diels-Alder Reaction

• Diels-Alder reaction A cycloaddition reaction of
  a conjugated diene and certain types of double
  and triple bonds.
• dienophile Diene-loving.
• Diels-Alder adduct The product of a Diels-Alder
  reaction.

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Diels-Alder Reaction

• Alkynes also function as dienophiles.
• Cycloaddition reaction A reaction in which two
  reactants add together in a single step to form a
  cyclic product.

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Diels-Alder Reaction

• We write a Diels-Alder reaction in the following
  way
• The special value of D-A reactions are that they
  
• 1. form six-membered rings.
• 2. form two new C-C bonds at the same time.
• 3. are stereospecific and regioselective.
• Note the reaction of butadiene and ethylene
  gives only traces of cyclohexene.

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Diels-Alder Reaction

• The conformation of the diene must be s-cis.

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Diels-Alder Reaction Steric Restrictions

• (2Z,4Z)-2,4-Hexadiene is unreactive in
  Diels-Alder reactions because nonbonded
  interactions prevent it from assuming the planar
  s-cis conformation.

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Diels-Alder Reaction

• Reaction is facilitated by a combination of
  electron-withdrawing substituents on one reactant
  and electron-releasing substituents on the other.

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Diels-Alder Reaction
29
Diels-Alder Reaction

• The Diels-Alder reaction can be used to form
  bicyclic systems.

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Diels-Alder Reaction

• Exo and endo are relative to the double bond
  derived from the diene.

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Diels-Alder Reaction

• For a Diels-Alder reaction under kinetic control,
  endo orientation of the dienophile is favored.

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Diels-Alder Reaction

• The configuration of the dienophile is retained.

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Diels-Alder Reaction

• The configuration of the diene is retained.

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Diels-Alder Reaction

• Mechanism
• No evidence for the participation of either
  radical of ionic intermediates.
• Chemists propose that the Diels-Alder reaction is
  a concerted pericyclic reaction.
• Pericyclic reaction A reaction that takes place
  in a single step, without intermediates, and
  involves a cyclic redistribution of bonding
  electrons.
• Concerted reaction All bond making and bond
  breaking occurs simultaneously.

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Diels-Alder Reaction

• Mechanism of the Diels-Alder reaction

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Aromatic Transition States

• Hückel criteria for aromaticity The presence of
  (4n 2) pi electrons in a ring that is planar
  and fully conjugated.
• Just as aromaticity imparts a special stability
  to certain types of molecules and ions, the
  presence of (4n 2) electrons in a cyclic
  transition state imparts a special stability to
  certain types of transition states.
• Reactions involving 2, 6, 10, 14.... electrons in
  a cyclic transition state have especially low
  activation energies and take place particularly
  readily.

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Aromatic Transition States

• Decarboxylation of ?-keto acids and
  ?-dicarboxylic acids.
• Cope elimination of amine N-oxides.

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Aromatic Transition States

• the Diels-Alder reaction
• pyrolysis of esters (Problem 22.42)
• We now look at examples of two more reactions
  that proceed by aromatic transition states
• Claisen rearrangement.
• Cope rearrangement.

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Claisen Rearrangement

• Claisen rearrangement A thermal rearrangement of
  allyl phenyl ethers to 2-allylphenols.

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Claisen Rearrangement
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Cope Rearrangement

• Cope rearrangement A thermal isomerization of
  1,5-dienes.

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Cope Rearrangement

• Example 24.8 Predict the product of these Cope
  rearrangements.

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Synthesis of Single Enantiomers

• We have stressed throughout the text that the
  synthesis of chiral products from achiral
  starting materials and under achiral reaction
  conditions of necessity gives enantiomers as a
  racemic mixture.
• Nature achieves the synthesis of single
  enantiomers by using enzymes, which create a
  chiral environment in which reaction takes place.
• Enzymes show high enantiomeric and diastereomeric
  selectivity with the result that enzyme-catalyzed
  reactions invariably give only one of all
  possible stereoisomers.

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Synthesis of Single Enantiomers

• How do chemists achieve the synthesis of single
  enantiomers?
• The most common method is to produce a racemic
  mixture and then resolve it. How?
• the different physical properties of
  diastereomeric salts.
• the use of enzymes as resolving agents.
• chromatographic on a chiral substrate.

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Synthesis of Single Enantiomers

• In a second strategy, asymmetric induction, the
  achiral starting material is placed in a chiral
  environment by reacting it with a chiral
  auxiliary. Later it will be removed.
• E. J. Corey used this chiral auxiliary to direct
  an asymmetric Diels-Alder reaction.
• 8-Phenylmenthol was prepared from naturally
  occurring enantiomerically pure menthol.

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Synthesis of Single Enantiomers

• The initial step in Coreys prostaglandin
  synthesis was a Diels-Alder reaction.
• By binding the achiral acrylate with
  enantiomerically pure 8-phenylmenthol, he thus
  placed the dienophile in a chiral environment.
• The result is an enantioselective synthesis.

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Synthesis of Single Enantiomers

• A third strategy is to begin a synthesis with an
  enantiomerically pure starting material.
• Gilbert Stork began his prostaglandin synthesis
  with the naturally occurring, enantiomerically
  pure D-erythrose.
• This four-carbon building block has the R
  configuration at each stereocenter.
• With these two stereocenters thus established, he
  then used well understood reactions to synthesize
  his target molecule in enantiomerically pure form.