Clemmensen Reduction
Introduction
Clemmensen reduction is an organic chemical reaction that uses zinc amalgam to reduce the carbonyl group in an aldehyde or ketone to a methylene group under heated reflux conditions in a concentrated hydrochloric acid solution.[1] The reaction is named after its discoverer, Danish-American chemist Erik Christian Clemmensen.[2]
Fig.1 Clemmensen Reduction
The conditions of the Clemmensen reduction reaction are particularly effective in the reduction of aryl alkyl ketones[3][4] (e.g., products in Friedel-Crafts acylation reactions) in such use scenarios. Therefore, the use of the Clemmensen reduction reaction in conjunction with the Friedel-Crafts acylation reaction is a classical strategy for the synthesis of alkyl aromatics.
Mechanism
Fig 2. Clemmensen reduction reaction mechanism
A mechanism of Clemmensen reduction was proposed in 1975.[5][6] The carbonyl group is first converted to a radical anion (shown in blue), then to a zinc carbene (shown in red), and then reduced to an alkane.
Although the reaction was discovered as early as 1914, the mechanism of the Clemmensen reduction reaction remains obscure to date. The non-homogeneous nature of the reaction itself has made it more difficult to study the reaction mechanism, and only a few studies have been published.[7,8] The two current mechanistic perspectives both involve organozinc intermediates, a carbon anion mechanism and a carbon-like mechanism.Brewster suggested the possibility of reduction reactions on metal surfaces. Depending on the structure of the carbonyl compound or the acidity of the reaction, a carbon-metal bond or an oxygen-metal bond is formed after the compound attaches to the metal surface.[7] In contrast, Vedeja proposed a reaction mechanism in which the radical anion and zinc-carbon compounds are first formed and then reduced to alkanes.[5,6] (as shown above) However, alcohols and carbons are not considered to be intermediates, and therefore, it is difficult to obtain alkane products from alcohols even under Clemenson reaction conditions. [7,9]
Application
Highly symmetrical hydrocarbons have attracted the interest of scientists because of their beautiful structures and potential applications, but many difficulties are still encountered in their synthesis.Suzuki et al. synthesized a hydrocarbon, Dibarrelane, using the Clemenson reduction reaction.[10] They set the secondary alcohol SN1 reaction took place, forming a chloride. Then, an excess of zinc reduced the chloride. Importantly, the reaction effectively reduced both ketones, alcohols and methoxycarbonyls, while avoiding the formation of by-products, giving the target product in high yield (61%).
Fig. 3 Synthesis of Dibarrelane [10]
The Clemenson reduction reaction is not particularly efficient for aliphatic compounds and cyclic ketones. An optimized reaction condition, in which activated zinc powder and hydrochloric acid are added to an anhydrous solution of ether or acetic anhydride, can improve the efficiency of the reduction reaction. In addition, the optimized Clemmensen reduction reaction allows selective deoxygenation of ketone groups in molecules containing stable groups such as cyano, amino, acetoxy, and alkoxycarbonyl groups. Yamamura et al. effectively reduced cholestan-3-ones to cholestanes using optimized Clemmensen reaction conditions and obtained the target products in high yields (76%) [11].
Fig.4. Reduction of cholestan-3-ones to cholestanes using the Clemenson reduction reaction[11].
Limitations of Clemson Response and Solutions
To use the Clemmensen reduction reaction, then the substrate needs to be able to withstand the strongly acidic conditions of the reaction (37% HCl). Two solutions are available. the Wolff-Kishner reduction reaction can reduce acid-sensitive substrates that are stable under strong base conditions; while substrates that are stable to hydrogenolysis under Raney nickel conditions can be reduced by the Mozingo reduction reaction to make thiol or thione, which can then be reduced with Raney nickel.
Reference
1. Smith, Michael (2007). March's advanced organic chemistry : reactions, mechanisms, and structure. Jerry March (6th ed.). Hoboken, N.J.: Wiley-Interscience.
2. 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. https://doi.org/10.1002/cber.19130460292\
3. "Y-PHENYLBUTYRIC ACID". Organic Syntheses. 15: 64. 1935. https://doi.org/10.15227/orgsyn.015.0064
4. "CREOSOL". Organic Syntheses. 33: 17. 1953. https://doi.org/10.15227/orgsyn.033.0017
5. 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, https://doi.org/10.1007/978-3-030-50865-4_31
6. 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, https://doi.org/10.1002/0471264180.or022.03
7. 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. https://doi.org/10.1021/ja01653a035
8. 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. https://doi.org/10.1021/ja01500a029
9. Martin, Elmore L. (2011), John Wiley & Sons, Inc. (ed.), "The Clemmensen Reduction", Organic Reactions, Hoboken, NJ, USA: John Wiley & Sons, Inc., pp. 155–209, https://doi.org/10.1002/0471264180.or001.07
10. 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. https://doi.org/10.1021/jo5003455
11. "MODIFIED CLEMMENSEN REDUCTION: CHOLESTANE". Organic Syntheses. 53: 86. 1973. https://doi.org/10.15227/orgsyn.053.0086.