Aldehydes and Ketones II' Oxidation and Reduction: Synthesis

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Synthesis of Aldehydes and Ketones
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Aldehydes can be prepared by reduction.

• This would be desirable to do
• The problem is, how to stop the reduction at the
  aldehyde state, without reducing all the way to a
  primary alcohol?

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Rosenmund Reduction
The catalyst is selectively poisoned. The
reaction generally goes in very good
yield. Quinoline is
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Example
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Another, similar, method uses a new reagent
Lithium Tri-tert-butoxy-aluminum Hydride
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• The tert-butyl groups provide steric hindrance.
• This diminishes the ability of the reagent to act
  as a hydride donor (as compared with LiAlH4).
• Also, there is only one reducing hydrogen per
  molecule of this reagent.

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Example
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Reduction of Esters to Aldehydes
An ester is reduced by lithium aluminum hydride
to yield two different alcohols
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• The lithium aluminum hydride reduces the acyl
  part of the ester to a primary alcohol.
• The alkyl part of the ester simply drops off as a
  second alcohol -- it is not reduced in this
  reaction.
• You would generally do this reaction to prepare
  the primary alcohol deriving from the acyl
  portion of the ester.

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• Lithium aluminum hydride is such a powerful
  reducing agent that it reduces the ester through
  two 2-electron reduction stages, all the way to
  the alcohol

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• Chemists have wondered if it might be possible to
  modify the structure of the aluminum hydride
  reducing agent so as to reduce an ester through
  one 2-electron reduction step, but no further.
• You have already seen a similar modification in
  the example of lithium tri-tert-butoxyaluminum
  hydride.

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Among the most useful modified aluminum hydride
reducing agents is Diisobutylaluminum Hydride,
also known as DIBALH.
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• Reductions are typically carried out in toluene
  or hexane solution at -78 C (dry ice-acetone
  bath).
• The reduction is followed by hydrolysis with
  aqueous acid to decompose the aluminum salts and
  liberate the aldehyde.
• After hydrolysis, the reaction is allowed to warm
  to room temperature.

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Reduction of Esters to Aldehydes
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In more detail...
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Reduction of esters with DIBALH has become a
valuable method for the synthesis of aldehydes.
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Example
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If the temperature of the reaction is not
maintained at dry ice temperatures, the ester
will be reduced all the way to the alcohol.
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This will not lose an alkoxy group at low
temperatures -- thus, no leaving group!
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Loss of the alkoxy group does not happen until
after the hydride reagent has been destroyed with
acid, so a second reduction step cannot
happen. Thus, temperature control is critical
for the selective reduction of an ester to an
aldehyde.
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Hydrolysis Step
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Nitriles can also be reduced to aldehydes, using
DIBALH
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Ketone Synthesis Using Organometallic Reagents

• We want to do
• Too bad it doesnt work! No ketone is obtained.

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Instead, we get alcohol
The Grignard reagent reacted twice.
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• The problem is that the organomagnesium reagent
  is too reactive -- we need something milder.
• So, we use an organocadmium reagent, instead

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Ketone Synthesis using Organocadmium Reagents
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Example
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Alternative
Apparently, both Grignard addition steps are too
slow at low temperature. But, the ferric
chloride catalyzes the first addition, making it
proceed fast enough to be useful. Ferric
chloride does not catalyze the second addition,
so it remains very slow and is not observed!
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Lithium dialkylcuprates can also be used to
prepare ketones from acid chlorides.
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Ketone Synthesis using Lithium Dialkylcuprates
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Example
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Synthesis Problem
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Another Synthesis Problem
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Are We Having Fun Yet?
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Lets Make Some Drugs!
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