User:Shiba111/Clemmensen reduction

Clemmensen Reduction
Clemmensen reduction is a chemical reaction described as a reduction of ketones (or aldehydes) to alkanes using zinc amalgam and concentrated hydrochloric acid (HCl). This reaction is named after Erik Christian Clemmensen, a Danish-American chemist.



Clemmensen reduction conditions are particularly effective at reducing aryl-alkyl ketones, such as those formed in a Friedel-Crafts acylation. The two-step sequence of Friedel-Crafts acylation followed by Clemmensen reduction constitutes a classical strategy for the primary alkylation of arenes.

Mechanism


Despite the reaction being first discovered in 1914, the mechanism of the Clemmensen reduction remains obscure. Due to the heterogeneous nature of the reaction, mechanistic studies are difficult, and only a handful of studies have been disclosed. Mechanistic proposals generally invoke organozinc intermediates, sometimes including zinc carbenoids, either as discrete species or as organic fragments bound to the zinc metal surface. Brewster proposed the possibility of the reduction occurring at the metal surface. Depending on the constitution of the carbonyl compound or the acidity of the reaction, a carbon-metal or oxygen-metal bond can form after the compound attaches to the metal surface. Furthermore, Vedeja proposed a mechanism involving the formation of radical anion and zinc carbenoid, followed by reduction to alkane (as shown above). However, alcohol and carbanion believe not to be intermediates, since exposing alcohol to Clemmensen conditions rarely affords the alkane product.

Application
Highly symmetrical hydrocarbon compounds have attracted much interest due to their beautiful structure, but the challenges in the synthesis persist. Suzuki et al. synthesized dibarrelane, a type of hydrocarbon compound, using Clemmensen reduction. They hypothesized that the secondary alcohol underwent an SN1 reaction, forming chloride. An excess amount of zinc reduces the chloride. Importantly, the reaction effectively reduced the two ketones, alcohol, and the methoxycarbonyl group while avoiding any by-products and gave the product in high yield (61%). Yamamura et al. used a modified Clemmensen reduction to reduce aliphatic or cyclic ketones. The modified conditions involves the activated zinc dust in an anhydrous solution of hydrogen chloride in diethyl ether or acetic anhydride, resulting in a much more effective reduction.

Problem and alternative approaches
To perform the Clemmensen reduction, the substrate must be tolerant of the strongly acidic conditions of the reaction (37% HCl). Several alternatives are available. Wolff-Kishner reduction can reduce acid-sensitive substrates that are stable to strong bases. For substrates stable to hydrogenolysis in the presence of Raney nickel, a milder two-step Mozingo reduction method is available.