WWU -- Chemistry Synthesis of Aldehydes and Ketones

WWU -- Chemistry 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?

WWU -- Chemistry Rosenmund Reduction The catalyst is selectively poisoned. The reaction generally goes in very good yield. Quinoline is:

WWU -- Chemistry Example

Another, similar, method uses a new reagent: Lithium Tri-tert-butoxy- aluminum Hydride

WWU -- Chemistry The tert-butyl groups provide steric hindrance. This diminishes the ability of the reagent to act as a hydride donor (as compared with LiAlH 4 ). Also, there is only one reducing hydrogen per molecule of this reagent.

WWU -- Chemistry Example

Reduction of Esters to Aldehydes An ester is reduced by lithium aluminum hydride to yield two different alcohols:

WWU -- Chemistry

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.

WWU -- Chemistry 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

WWU -- Chemistry 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.

WWU -- Chemistry Among the most useful modified aluminum hydride reducing agents is Diisobutylaluminum Hydride, also known as DIBALH.

WWU -- Chemistry 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.

WWU -- Chemistry Reduction of Esters to Aldehydes

WWU -- Chemistry In more detail...

WWU -- Chemistry Reduction of esters with DIBALH has become a valuable method for the synthesis of aldehydes.

WWU -- Chemistry Example

If the temperature of the reaction is not maintained at dry ice temperatures, the ester will be reduced all the way to the alcohol.

WWU -- Chemistry This will not lose an alkoxy group at low temperatures -- thus, no leaving group!

WWU -- Chemistry 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.

WWU -- Chemistry Hydrolysis Step

WWU -- Chemistry Nitriles can also be reduced to aldehydes, using DIBALH

WWU -- Chemistry Ketone Synthesis Using Organometallic Reagents We want to do: Too bad it doesn’t work! No ketone is obtained.

WWU -- Chemistry Instead, we get alcohol: The Grignard reagent reacted twice.

WWU -- Chemistry The problem is that the organomagnesium reagent is too reactive -- we need something milder. So, we use an organocadmium reagent, instead:

WWU -- Chemistry Ketone Synthesis using Organocadmium Reagents

WWU -- Chemistry Example

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!

WWU -- Chemistry Lithium dialkylcuprates can also be used to prepare ketones from acid chlorides.

WWU -- Chemistry Ketone Synthesis using Lithium Dialkylcuprates

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Synthesis Problem

WWU -- Chemistry Another Synthesis Problem

WWU -- Chemistry Are We Having Fun Yet?

WWU -- Chemistry Let’s Make Some Drugs!

WWU -- Chemistry