Reduction of Carboxylic Acids and Their Derivatives

UAIH4 is a strong reducing agent. DIBAL-H and LiAIH[OC(CH3)3]3 are milder, more selective reducing agents. 

Acid chlorides and esters can be reduced to either aldehydes or 1° alcohols, depending on the reagent. 

A milder reducing agent (DIBAL-H or LiAIH[OC(CH3)3j3) converts RCOCI or RCOOR to RCHO at low temperatures. 

In the reduction of an acid chloride. Cl comes off as the leaving group. strong reducing agent 

NADH is a coenzyme, an organic molecule that can function only in the presence of an enzyme. The active site of the enzyme binds both the carbonyl substrate and NADH, keeping them in close proximity. NADH then donates H in much the same way as a metal hydride reagent that is, reduction consists of nucleophihc attack followed by protonation. 

Pyruvic acid is formed during the metaboiism of giucose. During periods of strenuous exercise, when there is insufficient oxygen to metaboiize pyruvic acid to CO2, pyruvic acid is reduced to iactic acid. The tired feeiing of sore muscies is a resuit of iactic acid accumuiation. 

This reaction is completely enantioselective. For example, reduction of pyruvic acid with NADH catalyzed by lactate dehydrogenase affords a single enantiomer of lactic acid with the S configuration. NADH reduces a variety of different carbonyl compounds in biological systems. The configuration of the product (R or S) depends on the enzyme used to catalyze the process. 

Niacin can be obtained from foods such as soybeans, which contain it naturaiiy, and from breakfast cereais, which are fortified with it. 

the oxidized form of NADH, is a biological oxidizing agent capabie of oxidizing alcohols to carbonyl compounds (it forms NADH in the process). NAD is synthesized from the vitamin niacin, which can be obtained from soybeans among other dietary sources. Breakfast cereals are fortified with niacin to help people consume their recommended daily allowance of this B vitamin. 

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J. S. Cha, Recent Developments in the Synthesis of Aldehydes by Reduction of Carboxylic Acids and their Derivatives with Metal Hydrides, Org. Prep. Proced. Int. 1989, 21, 451- 477. 

The reduction of carboxylic acids and their derivatives gives a variety of products, depending on the identity of Z and the nature of the reducing agent. The usual products are aldehydes or 1 alcohols. 

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. 

The central problem in the reduction of carboxylic acids and their derivatives to aldehydes is the avoidance of overreduction to primary alcohols. The difficulty is particularly acute when, as in the case of the carboxylic acids themselves, the substrates are not especially reactive towards reducing agents. Thus there are few nonhydride methods of reducing carboxylic acids to aldehydes, and none which are routinely used. Those which are available generally have some specific feature which results in the trapping or protection of the product aldehydes. 

This chapter is concerned with the cathodic reduction of carboxylic acids and their derivatives, that is, esters, amides, anhydrides, acyl halides, hydrazides, nitriles, and corresponding thio derivatives. Cyclic derivatives of substituted carboxylic and polycarboxylic acids, such as lactones, lactams, imides, and anhydrides, are also included. Only those transformations in which the functional group itself is involved are discussed. Reductive coupling of carboxylic acids and derivatives is covered in Chapter 22, and there is some overlap with reduction of heterocycles in Chapter 18. 

Effective and selective reductions of carboxylic acids and their derivatives by eight categories of sodium borohydride reduction systems have been reviewed. The recent progress in establishing reaction mechanism and optimum conditions, as well as the reduction capacity and scope of application of the reduction systems has been discussed. i ... 

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