Reduction of carboxylic acids

Carboxylic acids are reduced by LiAlH4 (but not by NaBH4) to yield primary alcohols (Section 17.5). The reaction is difficult, however, and often requires heating in tetrahydrofuran solvent to go to completion. 

Alternatively, borane in tetrahydrofuran (BH/THF) is a useful reagent for reducing carboxylic acids to primary alcohols. Reaction of an acid with BH3/THF occurs rapidly at room temperature, and the procedure is often preferred to reduction with LiAlH because of its relative ease, safety, and specificity. Borane reacts with carboxylic acids faster than with any other functional group, thereby allowing selective transformations such as that shown below on p-nitrophenylacetic acid. If the reduction of p-nitrophenyl-acetic acid were done with LiAlH4, both nitro and carboxyl groups would be reduced. 

Problem 20.10 How might you prepare 2-phenylethanol from benzyl bromide More than one. step is required. 

Problem 20.11 How might you carry out the following transformation More than one step is required. 

The carboxylic group in carboxylic acids can be reduced to an aldehyde group, to an alcoholic group and even to a methyl group. Unsaturated acids and aromatic acids can be reduced at the multiple bonds or aromatic rings. 

Aromatic and aliphatic carboxylic acids are reduced to the trifluoroacetates of the alcohol with Et3SiH/TFA.277 Use of an excess of the triethylsilane can give 

The highly reactive reagent combination of Et3SiH/(C6F5)3B reduces carboxylic acids to methyl groups (Eq. 134).281,282 Isolation of the intermediate silyl ether is also possible.282 

Step 2 Nucleophilic attack on the methyl group displaces nitrogea O  

Because diazomethane is hazardous in large quantities, it is rarely used industrially or in large-scale laboratory reactions. The yields of methyl esters are excellent, however, so diazomethane is often used for small-scale esterifications of valuable and delicate carboxylic acids. 

Amides can be synthesized directly from carboxylic acids, using heat to drive off water 20-12 

Heating this salt to well above 100°C drives off steam and forms an amide. This direct AlTlinGS DiTGCt 

Show how to synthesize the following compounds, using appropriate carboxylic acids and amines. O 

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Lithium aluminium hydride, LiAlH, is a very active reducing agent, and is used particularly for the ready reduction of carboxylic acids (or their esters) to primary alcohols R-COOH -> R CH,OH. 

PREPARATION OF ALCOHOLS BY REDUCTION OF CARBOXYLIC ACIDS AND ESTERS... 

Reduction of Carboxylic Acids to Alcohols. In addition to the nonsupported catalysts mentioned for the hydrogenation of amides to amines, mthenium and rhenium on alumina can be used to reduce carboxyHc acids to alcohols. The conditions for this reduction are somewhat more severe than for most other hydrogenation reactions and require higher temperatures, >150° C, and pressures, >5 MPa (725 psi) (55). Various solvents can be used including water. 

Section 15.3 Alcohols can be prepared from carbonyl compounds by reduction of carboxylic acids and esters. See Table 15.3. 

Rhenium oxides are also useful in reduction of carboxylic acids (170" C, 3500 psig). Aromatic acids can be reduced to alcohols without ring saturation 3,4,S,6). Strongly synergistic effects were found on substituting half of the Re207 with rulhenium-on-carbon, and excellent results can be obtained al... 

The aldehyde intermediate can be isolated if 1 equivalent of diisobutvl-aluminum hydride (D1BAH) is used as the reducing agent instead of LiAlH4. The reaction has to be carried out at -78 °C to avoid further reduction to the alcohol. Such partial reductions of carboxylic acid derivatives to aldehydes also occur in numerous biological pathways, although the substrate is either a thioester or acyl phosphate rather than an ester. 

Reduction of Carboxylic Acids, Esters, and Anhydrides to Aldehydes ... 

With most reducing agents, reduction of carboxylic acids generally gives the primary alcohol (19-34) and the isolation of aldehydes is not feasible. However, simple straight-chain carboxylic acids have been reduced to aldehydesby treatment with Li in MeNH2 or NH3 followed by hydrolysis of the resulting imine, ... 

Reduction of carboxylic acids are the most difficult, but they can be accomplished with the powerful reducing agent lithium aluminum hydride (LiAlH4, abbreviated LAH). 

The reduction of carboxylic acids to the aldehydes is catalyzed by reduced viologen accepting tungsten containing enzymes from Clostridium thermoaceticum and Clostridium, formicoaceticum. This reaction is reversible [73-75] ... 

Reduction of carboxylic acids and esters, aldehydes, and nitriles, and the hydro-boration of alkenes with diborane in non-ethereal solvents is highly effective (Table 11.8), but reduction of nitro groups or cleavage of arena-halogen bonds does not occur [1]. However, in spite of the potential advantages, very little use appears to have been made of the procedure. 

The biocatalytic reduction of carboxylic acids to their respective aldehydes or alcohols is a relatively new biocatalytic process with the potential to replace conventional chemical processes that use toxic metal catalysts and noxious reagents. An enzyme known as carboxylic acid reductase (Car) from Nocardia sp. NRRL 5646 was cloned into Escherichia coli BL21(DE3). This E. coli based biocatalyst grows faster, expresses Car, and produces fewer side products than Nocardia. Although the enzyme itself can be used in small-scale reactions, whole E. coli cells containing Car and the natural cofactors ATP and NADPH, are easily used to reduce a wide range of carboxylic acids, conceivably at any scale. The biocatalytic reduction of vanillic acid to the commercially valuable product vanillin is used to illustrate the ease and efficiency of the recombinant Car E. coli reduction system." A comprehensive overview is given in Reference 6, and experimental details below are taken primarily from Reference 7. 

Reduction of Carboxylic Acids by Carboxylic Acid Reductase 297 Whole-cell Carboxylic Acid Reduction... 

Venkitasubramanian, P., Daniels, L. and Rosazza, J.P.N., Biocatalytic reduction of carboxylic acids mechanism and application. In Biocatalysis in the Pharmaceutical and Biotechnology Industries, Patel, R. (ed). CRC Press LLC Boca Raton, FL, 2006, pp. 425-440. 

Hydride as a nucleophile reduction of carboxylic acid derivatives... 

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