Alcohols by reduction of carbonyl compounds

Primary and secondary alcohols can be synthesized by the reduction of a variety of compounds that contain the carbonyl group. Several general examples are shown here  

Unless special precautions are taken, lithium aluminum hydride reductions can be very dangerous. You should consult an appropriate laboratory manual before attempting such a reduction, and the reaction should be carried out on a small scale. 

An example of lithium aluminum hydride reduction is conversion of 2,2-dimethylpropanoic acid to 2,2-dimethylpropanol (neopentyl alcohol). 

LAH reduction of an ester yields two alcohols, one derived from the carbonyl part of the ester group, and the other from the aUcoxyl part of the ester. 

Carboxylic acids and esters are more difficult to reduce than aldehydes and ketones. LAH, however, is a strong enough reducing agent to accomplish this transformation. Sodium borohydride (NaBH4), which we shall discuss shortly, is commonly used to reduce aldehydes and ketones, but it is not strong enough to reduce carboxylic acids and esters. 

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Table 7.1. Preparation of alcohols by reduction of carbonyl compounds.

Alcohols are generally prepared on insoluble supports by reduction of carbonyl compounds or by addition of carbon nucleophiles to carbonyl compounds, although other strategies have also been used (Figure 7.1). 

Alcohols are easily accessible by reduction of carbonyl compounds, such as aldehydes, ketones or carboxylic acid derivatives. While aldehydes, ketones and esters have been frequently used in microwave-assisted reductions, there have been no reports about the use of microwave technology in the reduction of nitriles or amides. 

Ionic routes to allylic (2) and benzylic (4) alcohols use reduction of carbonyl compounds (1) and (3) since these are readily available by condensation or Friedel-Crafts reaction. 

By Reduction of Carbonyl Compounds. Use of high (10 kbar) pressures has been shown to effect trialkylstannane reductions of ketones in the absence of radical initiators or Lewis acids.10 Zinc borohydride has been demonstrated to be a mild reducing agent for the conversion of benzenethiol esters into alcohols in good yield. Use of mixed solvents containing methanol has been found to confer some chemoselectivity upon reductions with lithium borohydride and permits enhanced rates of reduction of esters, lactones, and... 

Many biological processes involve oxidation of alcohols to carbonyl compounds or the reverse process reduction of carbonyl compounds to alcohols Ethanol for example is metabolized m the liver to acetaldehyde Such processes are catalyzed by enzymes the enzyme that catalyzes the oxidation of ethanol is called alcohol dehydrogenase... 

The introduction of tritium into molecules is most commonly achieved by reductive methods, including catalytic reduction by tritium gas, PH2], of olefins, catalytic reductive replacement of halogen (Cl, Br, or I) by H2, and metal pH] hydride reduction of carbonyl compounds, eg, ketones (qv) and some esters, to tritium-labeled alcohols (5). The use of tritium-labeled building blocks, eg, pH] methyl iodide and pH]-acetic anhydride, is an alternative route to the preparation of high specific activity, tritium-labeled compounds. The use of these techniques for the synthesis of radiolabeled receptor ligands, ie, dmgs and dmg analogues, has been described ia detail ia the Hterature (6,7). 

Ernst, M., Kaup, B., Mueller, M. et al. (2005) Enantioselective reduction of carbonyl compounds by whole-cell biotransformation, combining a formate dehydrogenase and a (R)-specihc alcohol dehydrogenase. Applied Microbiology and Biotechnology, 66 (6), 629-634. 

Rhin(bpy)3]3+ and its derivatives are able to reduce selectively NAD+ to 1,4-NADH in aqueous buffer.48-50 It is likely that a rhodium-hydride intermediate, e.g., [Rhni(bpy)2(H20)(H)]2+, acts as a hydride transfer agent in this catalytic process. This system has been coupled internally to the enzymatic reduction of carbonyl compounds using an alcohol dehydrogenase (HLADH) as an NADH-dependent enzyme (Scheme 4). The [Rhin(bpy)3]3+ derivative containing 2,2 -bipyridine-5-sulfonic acid as ligand gave the best results in terms of turnover number (46 turnovers for the metal catalyst, 101 for the cofactor), but was handicapped by slow reaction kinetics, with a maximum of five turnovers per day.50... 

The control of enantioselectivity in the reduction of carbonyl compounds provides an opportunity for obtaining the product alcohols in an enantiomerically enriched form. For transfer hydrogenation, such reactions have been dominated by the use of enantiomerically pure ruthenium complexes [33, 34], although Pfaltz and coworkers had shown by 1991 that high levels of enantioselectivity could be obtained using iridium(I) bis-oxazoline complexes [35]. 

Allylic acetates are usually prepared by esterification from allylic alcohols. However, the corresponding alcohols are often only accessible by the fairly expensive hydride reduction of carbonyl compounds. Consequently, direct allylic functionalization of easily available olefins has been intensively investigated. Most of these reactions involve peroxides or a variety of metal salts.However, serious drawbacks of these reactions, (e.g. toxicity of some metals, stoichiometric reaction conditions, or nongenerality) may be responsible for their infrequent use for the construction of allylic alcohols or acetates. 

Related examples are, for example, found in the area of catalyzed Diels-Alder reactions228. On reduction of carbonyl compounds by baker s yeast, in many cases hydrogen transfer occurs at the Re-face of the prostereogenic ketone 31 to yield alcohol 32 (Prelog s rule77). 

It is interesting that electrocatalyzed reduction of carbonyl compounds to alcohols takes place by using trialkoxysilanes (equation 101)128. 

Addition of hydrosilane to alkenes, dienes and alkynes is called hydrosilylation, or hydrosilation, and is a commercially important process for the production of many organosilicon compounds. As related reactions, silylformylation of alkynes is treated in Section 7.1.2, and the reduction of carbonyl compounds to alcohols by hydrosilylation is treated in Section 10.2. Compared with other hydrometallations discussed so far, hydrosilylation is sluggish and proceeds satisfactorily only in the presence of catalysts [214], Chloroplatinic acid is the most active catalyst and the hydrosilylation of alkenes catalysed by E PtCU is operated commercially [215]. Colloidal Pt is said to be an active catalytic species. Even the internal alkenes 558 can be hydrosilylated in the presence of a Pt catalyst with concomitant isomerization of the double bond from an internal to a terminal position to give terminal silylalkanes 559. The oxidative addition of hydrosilane to form R Si—Pt—H 560 is the first step of the hydrosilylation, and insertion of alkenes to the Pt—H bond gives 561, and the alkylsilane 562 is obtained by reductive elimination. 

Dichloroindium hydride (Cl2InH), generated by the reaction of InCl3 with tributyltin hydride, is also successfully used for the reduction of carbonyl compounds and for the debromination of alkyl bromides.366 This reductant has features such as the chemoselective reduction of functionalized benzaldehydes, chelation-controlled reduction of benzoin methyl ether, and 1,4-reduction of chalcone. The stable carbene and tertiary phosphine adducts of indium trihydride, InH3 CN(Mes)CH=CHN(Mes) and InH3 P(c-G6H11)3, reduce ketones to alcohols (Equation (90)).367... 

The reaction differs from the Ritter reaction by the two types of electrophilic activation of the reagents and by the two types of rearrangement of nitrilium 285 and carboxonium ions 288 (equation 94). Besides, this interaction proceeds at an oxidation level of two, while the Ritter reaction occurs at an oxidation level of one17. While it may be shown that A-acyliminium ions 365 can be obtained from a carbonyl compound and a nitrile via the Ritter reaction, then it is only the second step b) in a three-step process where the first step (a) is the reduction of carbonyl compound 364 to alcohol 366 and the third step (c) is an oxidative dehydrogenation of amide 369 obtained3 (equation 105). 

Although catalytic hydrogenation in the presence of H2 and a catalyst such as Pt, Pd, Ni or Ru, reaction with diborane, and reduction by lithium, sodium or potassium in hydroxylic or amine solvents have all been reported to convert carbonyl compounds into alcohols, the most common reagents used for the reduction of carbonyl compounds are hydride donors. 

Reduction of Carbonyl Compounds by Alcohols (Meerwein-Ponndorf-... 

Alcohols may be prepared by the hydrolysis of alkyl halides and esters, the reduction of carbonyl compounds, the addition of carbanions to carbonyl groups and the hydration of alkenes. Although these reactions are discussed in detail in the separate sections concerning these functional groups, they are brought together here to show the inter-relationship of these functional groups with alcohols. 

In terms of synthetic utility, the reduction of carbonyl compounds by a dissolving metal in liquid NH3 in the presence of an alcohol, water or NH4CI is far more common and usually far more efficient than reduction in the absence of a proton donor. Historically these reductions were carried out using active metals, usually Na, in alcohols and the experimental results are similar in both systems. - ... 

As noted above (Section 1.4.2.2) reduction of carbonyl compounds under these conditions proceeds with hydrogen transfer to afford an equimolar mixture of alkoxide and enolate, plus varying quantities of dimeric reduction products. As a consequence, at least in theory, this procedure should afford an equimolar mixture of recovered ketone and reduction product. This appears to be the case if less than one equivalent of metal is used however, with excess metal, camphor, " some 12-keto steroids2 and several 1 -decalones2 afforded 70-99% yields of secondary alcohols. The explanation which has been offered is that the product enolate is protonated by NH3 to regenerate the starting ketone, which is recycled through the reduction process. ... 

Early work by Papa et al. indicated that reduction of carbonyl compounds with Raney nickel in alkaline solution gave the corresponding hydrocarbon or alcohol products, and formation of the hydrocarbon was only feasible in the case of aromatic carbonyl compounds at 80-90 C. Mitchell et al. reported an improved method under neutral conditions using W-7 Raney nickel in 50% aqueous ethanol, aryl aldehydes, alkyl aryl and diaryl ketones can be reduced to the methylene products in high yields. Aromatic substituents such as nitro, cyano and halogen also suffer reduction under these conditions. 

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