Clemmensen reduction

Clemmensen reduction
Named after Erik Christian Clemmensen
Reaction type Organic redox reaction
Reaction
Ketone or Aldehyde
+
Zn(Hg)
+
HCl
↓
Reduction product
Conditions
Catalyst
+Δ
Identifiers
Organic Chemistry Portal clemmensen-reduction
RSC ontology ID RXNO:0000038

Clemmensen reduction is a chemical reaction described as a reduction of ketones or aldehydes to alkanes using zinc amalgam and concentrated hydrochloric acid (HCl).[1][2] This reaction is named after Erik Christian Clemmensen, a Danish-American chemist.[3]

The Clemmensen reduction
Scheme 1: Reaction scheme of Clemmensen Reduction.

Clemmensen reduction conditions are particularly effective at reducing aryl[4]-alkyl ketones,[5][6] 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

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Scheme 2: A mechanism of Clemmensen reduction was proposed in 1975.[7][8] The carbonyl is first converted to radical anion (shown as blue), then to zinc carbenoid (shown as red), and then reduced to alkane.

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.[9][10] 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.[9] Furthermore, Vedeja proposed a mechanism involving the formation of radical anion and zinc carbenoid, followed by reduction to alkane[7][8] (as shown above). However, alcohol and carbanion are not believed to be intermediates, since exposing alcohol to Clemmensen conditions rarely affords the alkane product.[9][11]

Application

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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.[12] They hypothesized that the secondary alcohol underwent an SN1 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%).

Scheme 3: The synthesis of Dibarrelane.[12]

Clemmensen 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%).[13]

Scheme 4: Reducing cholestane-3-one to cholestane using Clemmensen reduction.[13]

Problems and alternative approaches

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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.

Further reading

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  • Clemmensen, E. (1914). "Über eine allgemeine Methode zur Reduktion der Carbonylgruppe in Aldehyden und Ketonen zur Methylengruppe". Chemische Berichte. 47: 51–63. doi:10.1002/cber.19140470108.
  • Clemmensen, E. (1914). "Über eine allgemeine Methode zur Reduktion der Carbonylgruppe in Aldehyden und Ketonen zur Methylengruppe. (III. Mitteilung.)". Chemische Berichte. 47: 681–687. doi:10.1002/cber.191404701107.
  • Martin, E. L. (1942). "The Clemmensen reduction". Org. React. 1: 155.
  • Buchanan, J. G. St. C.; Woodgate, P. D. (1969). "The Clemmensen reduction of difunctional ketones". Quarterly Reviews, Chemical Society. 23 (4): 522. doi:10.1039/QR9692300522.
  • Vedejs, E. (1975). "Clemmensen reduction of ketones in anhydrous organic solvents". Org. React. 22: 401–422.
  • Yamamura, S.; Nishiyama, S. (1991). "Clemmensen Reduction". Comprehensive Organic Synthesis. 8: 309–313.
  • Burdon, J.; Price, R. C. (1986). "The Mechanism of the Clemmensen Reduction: the Substrates". Journal of the Chemical Society, Chemical Communications (12): 893–894. doi:10.1039/c39860000893 – via Royal Society of Chemistry.
  • Parikh, A.; Parikh, H.; Parikh, K. (2006). Name Reactions in Organic Synthesis. Foundation Books. pp. 115–117. doi:10.1017/UPO9788175968295.032. ISBN 9788175968295.
  • Carey, Francis A.; Sundberg, Richard J. (2007). Advanced Organic Chemistry: Part B: Reactions and Synthesis (5th ed.). New York: Springer. p. 453. ISBN 978-0387683546.

See also

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References

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  1. ^ Smith, Michael (2007). March's advanced organic chemistry : reactions, mechanisms, and structure. Jerry March (6th ed.). Hoboken, N.J.: Wiley-Interscience. p. 1835. ISBN 978-0-471-72091-1. OCLC 69020965.
  2. ^ Carey, Francis A.; Sundberg, Richard J. (2007). Advanced Organic Chemistry: Part B: Reactions and Synthesis (5th ed.). New York: Springer. p. 453. ISBN 978-0387683546.
  3. ^ Clemmensen, Erik (1913). "Reduktion von Ketonen und Aldehyden zu den entsprechenden Kohlenwasserstoffen unter Anwendung von amalgamiertem Zink und Salzsäure". Berichte der Deutschen Chemischen Gesellschaft. 46 (2): 1837–1843. doi:10.1002/cber.19130460292. ISSN 0365-9496.
  4. ^ Carey, Francis A.; Sundberg, Richard J. (2007). Advanced Organic Chemistry: Part B: Reactions and Synthesis (5th ed.). New York: Springer. p. 453. ISBN 978-0387683546.
  5. ^ "Y-Phenylbutyric Acid". Organic Syntheses. 15: 64. 1935. doi:10.15227/orgsyn.015.0064. ISSN 0078-6209.
  6. ^ "CREOSOL". Organic Syntheses. 33: 17. 1953. doi:10.15227/orgsyn.033.0017. ISSN 0078-6209.
  7. ^ a b Li, Jie Jack (2021), Li, Jie Jack (ed.), "Clemmensen Reduction", Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications, Cham: Springer International Publishing, pp. 109–111, doi:10.1007/978-3-030-50865-4_31, ISBN 978-3-030-50865-4, S2CID 243452810, retrieved 2023-04-01
  8. ^ a b Vedejs, E. (1975), John Wiley & Sons, Inc. (ed.), "Clemmensen Reduction of Ketones in Anhydrous Organic Solvents", Organic Reactions, Hoboken, NJ, USA: John Wiley & Sons, Inc., pp. 401–422, doi:10.1002/0471264180.or022.03, ISBN 978-0-471-26418-7, retrieved 2023-04-01
  9. ^ a b c Brewster, James H. (1954). "Reductions at Metal Surfaces. II. A Mechanism for the Clemmensen Reduction 1". Journal of the American Chemical Society. 76 (24): 6364–6368. doi:10.1021/ja01653a035. ISSN 0002-7863.
  10. ^ Nakabayashi, Tadaaki (1960). "Studies on the Mechanism of Clemmensen Reduction. I. The Kinetics of Clemmensen Reduction of p-Hydroxyacetophenone". Journal of the American Chemical Society. 82 (15): 3900–3906. doi:10.1021/ja01500a029. ISSN 0002-7863.
  11. ^ Martin, Elmore L. (2011), John Wiley & Sons, Inc. (ed.), "The Clemmensen Reduction", Organic Reactions, Hoboken, NJ, USA: John Wiley & Sons, Inc., pp. 155–209, doi:10.1002/0471264180.or001.07, ISBN 978-0-471-26418-7, retrieved 2023-03-31
  12. ^ a b Suzuki, Takahiro; Okuyama, Hiroshi; Takano, Atsuhiro; Suzuki, Shinya; Shimizu, Isao; Kobayashi, Susumu (2014-03-21). "Synthesis of Dibarrelane, a Dibicyclo[2.2.2]octane Hydrocarbon". The Journal of Organic Chemistry. 79 (6): 2803–2808. doi:10.1021/jo5003455. ISSN 0022-3263. PMID 24564301.
  13. ^ a b "Modified Clemmensen Reduction: Cholestane". Organic Syntheses. 53: 86. 1973. doi:10.15227/orgsyn.053.0086.
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