Clemmensen reduction

File:Clemmensen_Reduction.png

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.{{Cite journal |last=Brewster |first=James H. |year=1954 |title=Reductions at Metal Surfaces. II. A Mechanism for the Clemmensen Reduction 1 |url=https://pubs.acs.org/doi/abs/10.1021/ja01653a035 |journal=Journal of the American Chemical Society |language=en |volume=76 |issue=24 |pages=6364–6368 |doi=10.1021/ja01653a035 |issn=0002-7863}}{{Cite journal |last=Nakabayashi |first=Tadaaki |year=1960 |title=Studies on the Mechanism of Clemmensen Reduction. I. The Kinetics of Clemmensen Reduction of p-Hydroxyacetophenone |url=https://pubs.acs.org/doi/abs/10.1021/ja01500a029 |journal=Journal of the American Chemical Society |language=en |volume=82 |issue=15 |pages=3900–3906 |doi=10.1021/ja01500a029 |issn=0002-7863}} 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 are not believed to be intermediates, since exposing alcohol to Clemmensen conditions rarely affords the alkane product.{{Citation |last=Martin |first=Elmore L. |title=The Clemmensen Reduction |date=2011 |url=https://onlinelibrary.wiley.com/doi/10.1002/0471264180.or001.07 |work=Organic Reactions |pages=155–209 |editor-last=John Wiley & Sons, Inc. |access-date=2023-03-31 |place=Hoboken, NJ, USA |publisher=John Wiley & Sons, Inc. |language=en |doi=10.1002/0471264180.or001.07 |isbn=978-0-471-26418-7}}

Highly symmetrical hydrocarbon compounds have attracted much interest due to their beautiful structure and potential applications, but the challenges in the synthesis persist. Suzuki et al. synthesized dibarrelane, a type of hydrocarbon compound, using Clemmensen reduction.{{Cite journal |last1=Suzuki |first1=Takahiro |last2=Okuyama |first2=Hiroshi |last3=Takano |first3=Atsuhiro |last4=Suzuki |first4=Shinya |last5=Shimizu |first5=Isao |last6=Kobayashi |first6=Susumu |date=2014-03-21 |title=Synthesis of Dibarrelane, a Dibicyclo[2.2.2]octane Hydrocarbon |url=https://pubs.acs.org/doi/10.1021/jo5003455 |journal=The Journal of Organic Chemistry |language=en |volume=79 |issue=6 |pages=2803–2808 |doi=10.1021/jo5003455 |pmid=24564301 |issn=0022-3263}} They hypothesized that the secondary alcohol underwent an S_N1 reaction, forming a chloride. Then, an excess amount of zinc reduced the chloride. Importantly, the reaction effectively reduced the two ketones, alcohol, and the methoxycarbonyl group while avoiding any by-products, giving the product in high yield (61%).

File:Synthesis_of_dibarrelane.pngClemmensen reduction is not particularly effective with aliphatic or cyclic ketones. A modified condition, involving activated zinc dust in an anhydrous-solution of hydrogen chloride in diethyl ether or acetic anhydride, results in a more effective reduction. The modified Clemmensen reduction allows for the selective deoxygenation of ketones in molecules that contain stable groups such as cyano, amido, acetoxy, and carboalkoxy. Yamamura et al. effectively reduced cholestane-3-one to cholestane using the modified Clemmensen condition and gave the product in high yield (~76%).{{Cite journal |date=1973 |url=http://orgsyn.org/demo.aspx?prep=CV6P0289 |journal=Organic Syntheses |volume=53 |pages=86 |doi=10.15227/orgsyn.053.0086 |title=Modified Clemmensen Reduction: Cholestane }}

File:Modified_clemmensen_reduction_Cholestane.png using Clemmensen reduction.]]

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.

• {{cite journal

|author=Clemmensen, E.

|title=Über eine allgemeine Methode zur Reduktion der Carbonylgruppe in Aldehyden und Ketonen zur Methylengruppe

|journal=Chemische Berichte|year=1914|volume=47|pages=51–63

|doi=10.1002/cber.19140470108

|url=https://zenodo.org/record/1426539

}}

• {{cite journal

|author=Clemmensen, E.

|title=Über eine allgemeine Methode zur Reduktion der Carbonylgruppe in Aldehyden und Ketonen zur Methylengruppe. (III. Mitteilung.)

|journal=Chemische Berichte|year=1914|volume=47|pages=681–687

|doi=10.1002/cber.191404701107

|url=https://zenodo.org/record/1426541

}}

• {{cite journal|author=Martin, E. L.|title=The Clemmensen reduction | journal=Org. React.|year=1942|volume=1|page=155}}
• {{cite journal|author1=Buchanan, J. G. St. C. |author2=Woodgate, P. D. | journal=Quarterly Reviews, Chemical Society |year=1969|volume=23| issue=4 |page=522|doi=10.1039/QR9692300522|title=The Clemmensen reduction of difunctional ketones}}
• {{cite journal|author=Vedejs, E.| title=Clemmensen reduction of ketones in anhydrous organic solvents | journal=Org. React. |year=1975|volume=22|pages=401–422}}
• {{cite journal|author1=Yamamura, S. |author2=Nishiyama, S. | title=Clemmensen Reduction | journal=Comprehensive Organic Synthesis|year=1991|volume=8|pages=309–313}}
• {{Cite journal |last1=Burdon |first1=J. |last2=Price |first2=R. C. |date=1986 |title=The Mechanism of the Clemmensen Reduction: the Substrates |url=https://pubs.rsc.org/en/content/articlepdf/1986/c3/c39860000893 |journal=Journal of the Chemical Society, Chemical Communications |issue=12 |pages=893–894 |doi=10.1039/c39860000893 |via=Royal Society of Chemistry}}
• {{Cite book |last1=Parikh |first1=A. |title=Name Reactions in Organic Synthesis |last2=Parikh |first2=H. |last3=Parikh |first3=K. |publisher=Foundation Books |year=2006 |isbn=9788175968295 |pages=115–117 |doi=10.1017/UPO9788175968295.032}}
• {{cite book |ref=Carey |year=2007 |title=Advanced Organic Chemistry: Part B: Reactions and Synthesis |edition=5th |publisher=Springer |place=New York |author1=Carey, Francis A. |author2=Sundberg, Richard J. |isbn=978-0387683546|page=453}}

• Haworth phenanthrene synthesis
• Mozingo reduction
• Wolff-Kishner reduction
• Friedel-Crafts acylation

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{{Organic reactions}}

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Category:Organic reduction reactions

Category:Organic redox reactions