Clemmensen Reduction

In 1913, the Danish chemist Erik Christian Clemmensen reported that simple ketones and aldehydes reacted with amalgamated zinc (Zn/Hg) in the presence of 40% aqueous hydrochloric acid, and in a hydrophobic solvent, such as toluene, to give the corresponding alkanes after several hours under reflux conditions. Ever since, this method of converting carbonyl groups to the corresponding methylene group has been known as the Clemmensen reduction.

The Clemmensen reduction's original harsh conditions are not conducive to acid-sensitive substrates, so several modifications have been made to increase its synthetic utility by expanding the functional group tolerance. Yamamura and his colleagues developed a milder procedure using organic solvents such as tetrahydrofuran, saturated with hydrogen halides such as hydrogen chloride or bromide, in the presence of activated zinc dust at ice-bath temperatures.

Many heterocyclic 1,3-dicarbonyl compounds possessing alkyl substituents at the electronegative “2” position exhibit interesting biological properties. Synthesis of many of these molecules was expedited by Thomas Kappe and co-workers using a version of the Clemmensen reduction.