Reduction reactions carboxylic acids

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. 

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. 

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] ... 

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 9-42 Reduction of carboxylic esters 9-43 Reduction of carboxylic esters with titanocene dichloride 9-44 Reduction of anhydrides 9-45 Reduction of acyl halides 9-53 Reduction of nitriles 9-57 Reduction of hydroperoxides 9-60 Reduction of peroxides 9-69 Reaction between aldehydes and base (Cannizzaro)... 

The Reimer-Tiemann reaction is not an effective route to formyl-pyrroles or -indoles (see Section 3.05.1.6) and the oxidation of alkyl and hydroxyalkyl derivatives of the heterocycles and the reduction of carboxylic acid derivatives are discussed in Sections 3.05.2.2 and 3.05.2.4, respectively. 

From oxidative cleavage of 1,2-diols and 1,2-amino alcohols Dibutyltin oxide, 95 By reaction of alkyl halides with sulfur-stabilized carbanions Methylthiomethyl p-tolyl sulfone, 192 From reduction of carboxylic acids Vilsmeier reagent, 341 From terminal alkenes by addition reactions... 

An important example of this type of reaction is the formation of esters, which was discussed previously in connection with the reactions of alcohols in Section 15-4D. Similar addition-elimination mechanisms occur in many reactions at the carbonyl groups of acid derivatives. A less obvious example of addition to carboxyl groups involves hydride ion (H 0) and takes place in lithium aluminum hydride reduction of carboxylic acids (Sections 16-4E and 18-3C). 

Direct reduction of aldehydes with 2,3-dimethyl-2-butylborane proceeds rapidly and gives the corresponding alcohol. Nonetheless, reduction of carboxylic acids with the same borane (Section 18-3C) proceeds slowly and gives high yields of aldehydes. Explain why the reaction of RC02H with the 2,3-dimethyl-2-butylborane produces RCHO instead of RCH2OH. 

Reduction of carboxylic acids to aldehydes. 2 3-Acyllhiazolidine-2-thiones (2) can be prepared by reaction of l,3-thiazolidine-2-thione (1) with carboxylic acids directly (using 2-chloro-l-methylpyridinium iodide, 8, 95-96) or with acid chlorides (triethylamine or DCC). They can also be prepared from reaction of the thallium salt of 1 with an acid chloride. Yields by all four methods are 70-95%. The amides are reduced to aldehydes by either DIBAH or, generally in higher yield, by NaBH4 (90-98% yield). 

Fig. 6.43. Chemoselective reduction of carboxylic acid chloride to furnish an aldehyde the keto group of the substrate is compatible with these reaction conditions, too.

In summary, reductions of carboxylic acid derivatives to primary alcohols are usually accomplished by reaction of esters or acids with lithium aluminum hydride. The following equations provide several examples ... 

Selective reduction of—COOH to —CH2OH.2 Chemoselective reduction of carboxylic acids is possible by in situ conversion to the carboxymethyleneiminium salt by reaction with the Vilsmeier reagent (DMF and oxalyl chloride). This salt is then reduced with NaBH4 (2 equiv.) to the alcohol (equation I). Various functional groups are tolerated bromo, cyano, ester, and C=C (even when conjugated to COOH). 

Until about 1950, reduction of carboxylic acids and their derivatives to aldehydes was not straightforward, and even one of the best methods, the Rosenmund hydrogenation of acid chlorides, required very careful control of both the reaction conditions and preparation of catalyst. The advent of aluminum and boron hydrides and their ready commercial availability transformeKl the situation to such an extent that the formation of aldehydes from carboxylic acids, acid chlorides, esters, amides, nitriles and similar groups in the presence of other reducible functional groups has become a relatively easy operation on both small and large scale. 

In conceptually much the same sort of reaction, carboxylic acids have been treated with o-phenylene-diamine and then methyl iodide to yield benzimidazolium salts (51 Scheme 24). Reduction of the latter with NaBH4 gives the hydro compound (52), which can be hydrolyzed by dilute acid to give the aldehyde.For the few aldehydes described, yields were about 70%. 

There is no generally useful nonhydride method for the direct reduction of carboxylic acid esters to aldehydes. There are, however, procedures which are valuable under particular circumstances. An important example is the one-electron reduction of aldonolactones to aldoses. Two factors presumably contribute to the success of these reactions firstly the presence of electron-withdrawing substituents in the substrates, raising the reactivity of the carbonyl group, and secondly the ability of the products to form cyclic hemiacetals stable to further reduction. 

In a later development by Bedenbaugh et methylamine was used as solvent and lithium as electron donor. No proton donor was required, suggesting that the lithium salt (28) of hemiaminal (27) is stable under the reaction conditions (both aldehydes and aldimines are reduced by the reagent cf. the analogous reduction of carboxylic acids, Section 1.12.2 and Scheme 2). Yields of aldehydes produced by this method are shown in Table 8. It is notable that only tertiary amides are reduced satisfactorily. A major limitation of the reaction is the substantial formation of side products resulting from transamid-ation by the methylamine solvent (/. e. RCONHMe from RCONR 2). 

Reduction. The reagent is useful for reduction of carboxylic acid esters to primary alcohols. For example, the following esters have been reduced to the corresponding carbinols ethyl p-nitrobenzoate (96% yield), ethyl phenylacetate (90% yield), ethyl gly-cinate (70% yield). The reaction has some useful features Hydroxylic solvents (ethanol, water) can be used, the selectivity is higher than in the case of lithium aluminum hydride, and the reagent is nearly neutral. The reagent was found to be satisfactory for reduction of the dimethyl ester of 4,4 -dinitro-2,2 -diphenic acid (la) to the corresponding alcohol (lb, 51%yield).2... 

Reduction of carboxylic acids. Burgstahler et al. a few years ago reported briefly that carboxylic acids can be reduced to aldehydes by lithium and ethyl-amine however, the yields for the most part were low except in the case of fairly high molecular weight acids. Bedenbaugh et al.3 report that the reaction is actually of considerable value. They used methylamine rather than ethylamine and maintained a basic medium. Under these conditions an intermediate imine can be isolated. This intermediate is hydrolyzed rapidly by aqueous acids to an aldehyde or it can be reduced to the corresponding amine either catalytically or with lithium in methylamine. The conversions are illustrated for pentanoic acid as starting material. 

Kamochi and Kudo have reported the use of the Sml2/THF-H20 system to reduce aromatic carboxylic acids to alcohols (Scheme 50). Furthermore, aromatic esters amides and nitriles were similarly reduced by this system in good yield [104]. As indicated above, reduction of carboxylic acids to primary alcohols is also effective with Sml2 in a THF-H20-NaOH mixture [105]. In contrast, without water these substrates remain unchanged. With the Sml2/THF-H20 system, pyridine was rapidly reduced to piperidine in similar reactions with pyridine derivatives bearing chloro, amino and cyano substituents, these functionalities were partly eliminated to afford pyridine or piperidine [107]. 

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