The reduction of aldehydes and ketones

One procedure for the conversion of a carbonyl group to a methylene group is the Clemmensen reduction, and involves the use of zinc amalgam in the presence of concentrated hydrochloric acid. 

This represents a somewhat unusual reduction of a carbonyl group, which might be expected to give an alcohol with the metal-acid reducing system (cf. Section 5.4.1, p. 519). Alcohols are stable to the Clemmensen conditions and are not therefore intermediates in the reduction process, which is thought to proceed by a mechanism involving the formation of organo-zinc intermediates. A typical example is provided by the conversion of heptan-2-one to heptane (Expt 5.5). 

The method is often used for the reduction of aromatic carbonyl compounds (see 6.1.1, p. 827) which are reduced in good yield. Here the procedure is modified11 by the addition of a solvent immiscible with hydrochloric acid, i.e. toluene. 

When the Clemmensen method fails, or when strongly acidic conditions are precluded owing to the presence of acid-sensitive functional groups, the Wolff-Kishner reduction or the Huang-Minlon modification of it may succeed. The latter method is also discussed in Section 6.1.1, p. 827, and illustrated in Expt 6.4, Method A. 

An alternative procedure is to convert the carbonyl compound into the toluene-p-sulphonylhydrazone,12 followed by reduction with either sodium borohydride in acetic acid,13 or with catecholborane, followed by decomposition of the intermediate with sodium acetate or tetrabutylammonium acetate.14 The former method is illustrated by the conversion of undecan-6-one into undecane (Expt 5.6), and the latter by the conversion of acetophenone into ethylbenzene (Expt 6.4, Method B). A feature of these methods is that with a, / -unsaturated ketones, migration of the carbon-carbon multiple bond occurs thus the tosylhydrazone of isophorone gives 3,3,5-trimethylcyclohex-l-ene, and the tosylhydrazone of oct-3-yn-2-one gives octa-2,3-diene. 

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We will begin with the reduction of aldehydes and ketones... 

Addition of sodium dithionite to formaldehyde yields the sodium salt of hydroxymethanesulfinic acid [79-25-4] H0CH2S02Na, which retains the useful reducing character of the sodium dithionite although somewhat attenuated in reactivity. The most important organic chemistry of sodium dithionite involves its use in reducing dyes, eg, anthraquinone vat dyes, sulfur dyes, and indigo, to their soluble leuco forms (see Dyes, anthraquinone). Dithionite can reduce various chromophores that are not reduced by sulfite. Dithionite can be used for the reduction of aldehydes and ketones to alcohols (348). Quantitative studies have been made of the reduction potential of dithionite as a function of pH and the concentration of other salts (349,350). 

There are other stereochemical aspects to the reduction of aldehydes and ketones. If there is a chiral center to the carbonyl group, even an achiral reducing agent can give more of one diastereomer than of the other. Such diastereoselective reductions have been carried out with considerable success. In most such cases Cram s rule (p. 147) is followed, but exceptions are known. ... 

As with the reduction of aldehydes and ketones (16-23), the addition of organometallic compounds to these substrates can be carried out enantioselectively and diastereoselectively. Chiral secondary alcohols have been obtained with high ee values by addition to aromatic aldehydes of Grignard and organolithium compounds in the presence of optically active amino alcohols as ligands. ... 

As for some of the monodentate phosphine-based catalysts, ds-[Ru(6,6 -Cl2bpy)2(0H2)2][CF3S03]2 was found to require water for the best catalytic activity in the reduction of aldehydes and ketones [57]. Aldehydes and ketones were found to be hydrogenated, with reasonable yields. Unsaturated aldehydes were reduced with selectivity towards the unsaturated alcohol, whereas unsaturated ketones showed selectivity towards the saturated ketones. 

Enzyme reductions of carbonyl groups have important applications in the synthesis of chiral compounds (as described in Chapter 10). Dehydrogenases are enzymes that catalyse, for example, the reduction of carbonyl groups they require co-factors as their co-substrates. Dehydrogenase-catalysed transformations on a practical scale can be performed with purified enzymes or with whole cells, which avoid the use of added expensive co-factors. Bakers yeast is the whole cell system most often used for the reduction of aldehydes and ketones. Biocatalytic activity can also be used to reduce carbon carbon double bonds. Since the enzymes for this reduction are not commercially available, the majority of these experiments were performed with bakers yeast1 41. 

While ether is the common solvent for LiAlH4, in which it is soluble, hydroxylic solvents like water, methanol and ethanol are preferred for NaBH4, It is more soluble in methanol than in ethanol, but since it reacts with the former at an appreciable rate than the latter, hence ethanol is the preferred solvent. Isopropanol, in which NaBH4 is stable, is used for kinetic studies of the reduction of aldehydes and ketones. 

Seebach and Daum (75) investigated the properties of a chiral acyclic diol, 1,4-bis(dimethylamino)-(2S,35)- and (2K,3/ )-butane-2,3-diol (52) as a chiral auxiliary reagent for complexing with LAH. The diol is readily available from diethyl tartrate by conversion to the dimethylamide and reduction with LAH. The diol 52 could be converted to a 1 1 complex (53) with LAH (eq. [18]), which was used for the reduction of aldehydes and ketones in optical yields up to 75%. Since both enantiomers of 53 are available, dextro- or levorotatory products may be prepared. The chiral diol is readily recoverable without loss of optical activity. The (- )-52-LAH complex reduced dialkyl and aryl alkyl ketones to products enriched in the (S)-carbinol, whereas (+ )-52-LAH gives the opposite result. The highest optical yield of 75% was obtained in the reduction of 2,4,6-... 

You learned earlier that primary alcohols are oxidized to aldehydes, and secondary alcohols are oxidized to ketones. You can think of the reduction of aldehydes and ketones as the reverse of these reactions. Aldehydes can be reduced to produce primary alcohols. Ketones can be reduced to produce secondary alcohols. 

This procedure illustrates a general method for the reduction of aldehyde and ketone functions to methylene groups under very mild conditions. Since strong acids and bases are not employed, this procedure is of particular importance for the reduction of ketones possessing an adjacent chiral center. Moreover, the use of deuterated metal hydrides permits the preparation of labelled compounds. ... 

There are other stereochemical aspects to the reduction of aldehydes and ketones. If there is a chiral center a to the carbonyl group,309 even an achiral reducing agent can give... 

Varma reported a facile and rapid method for the reduction of aldehydes and ketones to the respective alcohols, using alumina-supported sodium borohydride and microwave irradiation under solvent-free conditions. Aldehydes tend to react at room temperature, while for the reduction of ketones, short microwave irradiation of 30-180 s was applied to produce the corresponding alcohols in 62-92% yield. With unsaturated carbonyl compounds, reduction at the conjugated C=C bond might occur as a side reaction under these conditions (Scheme 4.9)26. 

The production of alcohols by the reduction of aldehydes and ketones is probably one of the most useful and fundamental steps in the synthetic chemist s arsenal. Although there are many well developed methods for the reduction of ketones and aldehydes to alcohols, there is still much interest in developing new or improved methodologies which are milder and can be brought about under special conditions, especially in the presence of other reducible functional groups. Of particular interest to the modern synthetic organic chemist are the aldehyde and ketone reductions which are accomplished in an enantioselective fashion. Advances in this field up to 1992 have been the subject of a review by Singh198. The present section covers very recent work in this area. 

This section covers the reduction of aldehydes and ketones, in complex molecules using hydride transfer reagents. Many of these are complex reagents designed specifically for particular reactions. LAH has been used for the reduction of cyclopropyl ketones199. Trialkyltin moieties in the cyclopropane ring cause diastereoselective reduction to occur (equation 51). 

Lithium borohydride is intermediate in activity as a reducing agent between lithium aluminium hydride and sodium borohydride. In addition to the reduction of aldehydes and ketones it will readily reduce esters to alcohols. It can be prepared in situ by the addition of an equivalent quantity of lithium chloride to a 1m solution of sodium borohydride in diglyme. Lithium borohydride should be handled with as much caution as lithium aluminum hydride. It may react rapidly and violently with water contact with skin and clothing should be avoided. 

The reduction of aldehydes and ketones. Aromatic hydrocarbons are the main products when aromatic aldehydes or ketones are reduced with amalgamated zinc and concentrated hydrochloric acid (the Clemmensen reduction, e.g. hexylbenzene, Expt 6.3). 

Ketone and Aldehyde Reduction. In addition to the reduction of aldehyde and ketones through the reverse reaction of alcohol dehydrogenase, a family of aldehyde reductases also reduces these compounds. These reductases are NADPH-dependent, cytoplasmic enzymes of low molecular weight and have been found in liver, brain, kidney, and other tissues. 

The reduction of aldehydes and ketones to alkanes. Condensation of the carbonyl compound with hydrazine forms the hydrazone, and treatment with base induces the reduction of the carbon coupled with oxidation of the hydrazine to gaseous nitrogen, to yield the corresponding alkane. 

The reduction of aldehydes and ketones is carried out very easily. The carbonyl compound and aluminum isopropoxide, prepared from aluminum and isopropyl alcohol, are heated in boiling isopropyl alcohol solution with provision for slow distillation until no more acetone is formed. The general equation may be represented as follows. 

As in the catalytic method above, other functional groups susceptible (o reduction may interfere. In that case NaBIt., is the only choice since it is highly specific Tor the reduction of aldehydes and ketones. 

The use of lithium aluminum hydride or sodium borohydride provides the best method for the reduction of aldehydes and ketones to alcohols. 

Sml2 reduces aldehydes and ketones to the corresponding alcohols. As there are numerous hydride reducing agents for the reduction of aldehydes and ketones, this functional group transformation has not been used widely. In some cases, however, Sml2 can display useful reactivity, stereoselectivity and chemoselec-tivity that more conventional reagents cannot achieve. 

Carbonyl reductases and alcohol and aldehyde dehydrogenases are cytosolic enzymes being involved in the oxidation of alcohols and aldehydes and in the reduction of aldehydes and ketones (Lang and Kalgutkar 2003). 

The next two examples illustrate the reduction of aldehydes and ketones in the presence of other reactive functional groups. No reaction occurs at the nitro group in the first case or at the alkyl halide in the second. 

Hydrostannation. This triflate is a very effective catalyst for the reduction of aldehydes and ketones with Bu,SnH at room temperature in benzene or dichloroethane. Yields (85%-98%) are generally superior to those obtained with BujSnH and AIBN or BujSnH and CHjOH. The stereochemistry is similar to that observed with BujSnH-AIBN. Aldehydes can be reduced with high selectivity in the presence of a methyl ketone. Esters and ketals are not reduced. 

Aldehyde reductases, which catalyze the reduction of aldehydes and ketones, are widely distributed in animal species, including insects (e.g., D. melanogaster). These enzymes catalyze the reaction shown in Figure 8.16. 

The formation of alcohols by the reduction of aldehydes and ketones, carboxylic acids, esters and epoxides is summarized in Scheme 2.9. The change in the strength of the reducing agents, from the relatively mild sodium borohydride to the vigorous lithium aluminium hydride, reflects the difference in the electron deficiency of the carbonyl group which is being reduced. 

The reduction of aldehydes and ketones is a common reaction used in the synthesis of many useful natural products. Two examples are shown in Figure 20.2. 

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