Mechanism Clemmensen reduction

Guaiacols. Cresote, obtained from the pyrolysis of beechwood, and its active principles guaiacol [90-05-1] (1) and cresol [93-51-6] (2) have long been used ia expectorant mixtures. The compounds are usually classed as direct-acting or stimulant expectorants, but their mechanisms of action have not been well studied. Cresol is obtained by the Clemmensen reduction of vanillin (3), whereas guaiacol can be prepared by a number of methods including the mercuric oxide oxidation of lignin (qv) (4), the ziac chloride reduction of acetovanillone (5), and the diazotization and hydrolysis of o-anisidine (6). 

Not much is known about the mechanism of the Clemmensen reduction. Several mechanisms have been proposed, " including one going through a zinc-carbene intermediate. " One thing reasonably certain is that the corresponding alcohol is not an intermediate, since alcohols prepared in other ways fail to give the reaction. Note that the alcohol is not an intermediate in the Wolff-Kishner reduction either. 

In the Clemmensen reduction of 1,4-cyclohexanedione, all the products isolated from the reduction of 2,5-hexanedione were found in addition to 2,5-hexanedione (20%) and 2-methylcyclopentanone (6%). The presence of the two latter compounds reveals the mechanism of the reduction. In the first stage the carbon-carbon bond between carbons 2 and 3 ruptured, and the product of the cleavage, 2,5-hexanedione, partly underwent aldol condensation, partly its own further reduction [927], The cleavage of the carbon-carbon bond in 1,4-diketones was noticed during the treatment of 1,2-diben-zoylcyclobutane which afforded, on short refluxing with zinc dust and zinc chloride in ethanol, an 80% yield of 1,6-diphenyl-1,6-hexanedione [75<5]. 

We therefore use a dissolving metal reduction in strong acid. This reaction, the Clemmensen reduction, may use the principle we have outlined here, but its mechanism is unknown in detail. R2C = 0 + Zn/Hg + cone. HC1— )RaCH2... 

The mechanism of the Clemmensen reduction is not well understood. It is clear that in most cases the alcohol is not an intermediate, because the Clemmensen conditions do not suffice to reduce most alcohols to hydrocarbons. 

An alternative milder procedure is the reduction of the corresponding toluene-p-sulphonylhydrazones with catecholborane, followed by decomposition of the intermediate with sodium acetate in the presence of dimethyl sulphoxide, or with tetrabutylammonium acetate.1 These methods, which do not have the disadvantages of the Clemmensen reduction, are illustrated by the preparation of ethylbenzene from acetophenone (Expt 6.4, Methods A and B). Outline mechanisms for these reactions are given below. 

The reduction takes place at the surface of the zinc catalyst. In this reaction, alcohols are not postulated as intermediates, because subjection of the corresponding alcohols to these same reaction conditions does not lead to alkanes. The following proposal employs the intermediacy of zinc carbenoids to rationalize the mechanism of the Clemmensen Reduction ... 

Another reaction that can be used to accomplish the same transformation is the Wolff-Kishner reduction. In this procedure the aldehyde or ketone is heated with hydrazine and potassium hydroxide in a high boiling solvent. An example is provided in the following equation. (The mechanism for the Wolff-Kishner reduction is presented in Section 18.8.) The Clemmensen reduction and the Wolff-Kishner reduction are... 

As shown in Section I, Clemmensen reduction of quinolizidin-1 -one (1) gave perhydroazaazulene (3) instead of the expected quinolizidine (2). The mechanism of this rearrangement has been studied and the reaction has been used for a synthesis of azaazulene derivatives (61 Mil). 

Clemmensen Reduction (Review) The Clemmensen reduction commonly converts acylbenzenes (from Friedel-Crafts acylation, Section 17-1 IB) to alkylbenzenes, but it also works with other ketones and aldehydes that are not sensitive to acid. The carbonyl compound is heated with an excess of amalgamated zinc (zinc treated with mercury) and hydrochloric acid. The actual reduction occurs by a complex mechanism on the surface of the zinc. 

The third method is the simplest to do, but has the most complicated mechanism. The Clemmensen reduction is also rather violent, and really reasonable only for compounds with just the one functional group. It uses zinc metal dissolvmg in hydrochloric acid. As the metal dissolves, it gives up two electrons—in the absence of something else to do, these electrons would reduce the H+ in the acid to H2, and give ZnCl2 and H2. But in the presence of a carbonyl compound, the electrons go to reduce the C=0 bond. 

The Clemmensen reduction of saturated steroid ketones (zinc amalgam and hydrochloric acid) has not been examined in detail, although it was frequently used in early steroid chemistry to reduce a C==0 group to CH2 [37J. The mechanism inferred from studies on other ketones involves ratedetermining addition of zinc to the carbonyl group, and subsequent transformations of the type indicated (Fig. 28) [38]. 

The reaction mechanism of Clemmensen reduction has not completely been clarified, but it is well known that the alcohol is not an intermediate. As summarized in Scheme 3, the reduction is thought to occur on the zinc metal surface, and involves protonation of the carbonyl function and a concomitant... 

Electrolysis of carbonyl compounds provides pinacols, alcohols or hydrocarbons, depending on the conditions, such as pH, the nature of the electrode, and its potential. Fundamental studies have been carried out on the mechanisms of hydrocarbon formation using acetone as a substrate. Although several electrodes, such as Cd, Pt, Pb or Zn, are recommended, carbonyl compounds, including aryl and alkyl derivatives, require strong aqueous acidic media for reduction to the hydrocarbons. The mechanism of the electrolytic reduction is probably similar to that of Clemmensen reduction, which starts from anion radical formation by one-electron transfer, as indicated in Scheme 3. The difference is that electrolytic reduction takes place in an electric double layer, rather than on the surface of the zinc metal. 

In the case of aryl aldehydes and ketones, benzaldehyde afforded benzyl alcohol as the major product, but acetophenone and its para-substituted derivatives carrying such groups as OMe, Cl or OH provided ethylbenzene derivatives in good yields. As with Clemmensen reduction, the alcohol produced in this reduction cannot be further reduced, and the alcohol is not therefore an intermediate. Still uncertain in the reaction mechanism of electrolytic reduction, however, is the role of adsorbed hydrogen. ... 

Brewster, J. H., Patterson, J., Fidler, D. A. Mechanism of reductions at metal surfaces. III. Clemmensen reduction of some sterically hindered ketones. J. Am. Chem. Soc. 1954, 76, 6368-6371. 

Di Vona, M. L., Floris, B., Luchetti, L., Rosnati, V. Single-electron transfers in zinc-promoted reactions. The mechanisms of the Clemmensen reduction and related reactions. Tetrahedron Lett. 1990, 31, 6081-6084. 

It is not intended to give an exhaustive coverage of all possible reduction and oxidation reactions that are of synthetic utility in organic chemistry. Instead, the aim is to give a selection of reactions that will illustrate the major mechanistic pathways. In the case of redox reactions for organic molecules, there is a large number of cases for which the mechanism has not been studied in any detail, or if it has, no consensus has arisen as to the true pathway. This is even true for such an important synthetic reaction as the Clemmensen reduction... 

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