Lithium aluminum hydride, reducing carboxylic acids

The reduction of free acids to alcohols became practical only after the advent of complex hydrides. Lithium aluminum hydride reduces carboxylic acids to alcohols in ether solution very rapidly in an exothermic reaction. Because of the presence of acidic hydrogen in the carboxylic acid an additional equivalent of lithium aluminum hydride is needed beyond the amount required for the reduction. The stoichiometric ratio is 4 mol of the acid to 3 mol of lithium aluminum hydride (Equation 12, p. 18). Trimethylacetic add was reduced to neopentyl alcohol in 92% yield, and stearic acid to 1-octadecanol in 91% yield. Dicarboxylic sebacic acid was reduced to 1,10-decanedioI even if less than the needed amount of lithiiun aluminum hydride was used [968]. 

Lithium aluminum hydride reduces exclusively the carboxyl group, even in an unsaturated acid with a, -conjugated double bonds. Sorbic acid afforded 92% yield of sorbic alcohol [968], and fumaric acid gave 78% yield of trans-2-butene-l,4-diol [97S]. If, however, the a, -conjugated double bond of an add is at the same time conjugated with an aromatic ring it is reduced (p. 141). 

B is correct. The first equivalent of lithium aluminum hydride reduces the carboxylic acid to the primary alcohol, which is then completely reduced by the second equivalent of the hydride. The secondary alcohol does not reduce easily with lithium aluminum hydride. 

Lithium aluminum hydride reduces the carboxylic acid to the corresponding primary alcohol, compound E. Treatment of the vicinal chlorohydrin with base results in formation of an epoxide, compound F. 

We recall that LLAIH4 reduces esters of carboxylic acids, yielding primary alcohols (Section 15.9). An aldehyde occurs as an intermediate in the reaction, but cannot be isolated because lithium aluminum hydride reduces it more readily than the ester. Sodium borohydride does not reduce esters. 

Carboxylic acids are also reduced by lithium aluminum hydride. However, the acidic proton of the carboxylic acid reacts with one equivalent of hydride ion to generate hydrogen gas and a hthium salt of the carboxylic acid. This reaction destroys part of the hydride reagent. 

Carboxylic acids are exceedingly difficult to reduce Acetic acid for example is often used as a solvent in catalytic hydrogenations because it is inert under the reaction con ditions A very powerful reducing agent is required to convert a carboxylic acid to a pri mary alcohol Lithium aluminum hydride is that reducing agent... 

Sodium borohydride is not nearly as potent a hydride donor as lithium aluminum hydride and does not reduce carboxylic acids... 

Lithium aluminum hydride reduction (Sec tion 15 3) Carboxylic acids are reduced to primary alcohols by the powerful reducing agent lithium aluminum hydride... 

Generally, the carboxyl group is not readily reduced. Lithium aluminum hydride is one of the few reagents that can reduce these organic acids to alcohols. The scheme involves the formation of an alkoxide, which is hydroly2ed to the alcohol. Commercially, the alternative to direct reduction involves esterification of the acid followed by the reduction of the ester. 

In most other reactions the azolecarboxylic acids and their derivatives behave as expected (cf. Scheme 52) (37CB2309), although some acid chlorides can be obtained only as hydrochlorides. Thus imidazolecarboxylic acids show the normal reactions they can be converted into hydrazides, acid halides, amides and esters, and reduced by lithium aluminum hydride to alcohols (70AHC(12)103). Again, thiazole- and isothiazole-carboxylic acid derivatives show the normal range of reactions. 

Properly substituted isoxazolecarboxylic acids can be converted into esters, acid halides, amides and hydrazides, and reduced by lithium aluminum hydride to alcohols. For example, 3-methoxyisoxazole-5-carboxylic acid (212) reacted with thionyl chloride in DMF to give the acid chloride (213) (74ACS(B)636). Ethyl 3-ethyl-5-methylisoxazole-4-carboxylate (214) was reduced with LAH to give 3-ethyl-4-hydroxymethyl-5-methylisoxazole (215) (7308(53)70). 

The Rosenmund reduction is usually applied for the conversion of a carboxylic acid into the corresponding aldehyde via the acyl chloride. Alternatively a carboxylic acid may be reduced with lithium aluminum hydride to the alcohol, which in turn may then be oxidized to the aldehyde. Both routes require the preparation of an intermediate product and each route may have its advantages over the other, depending on substrate structure. 

Compared to the lithium enolates of l and 5, the higher stereoselectivity obtained by the Mukaiyama variation is, in general, accompanied by reduced chemical yields. The chiral alcoholic moieties of the esters 3 and 7 can be removed either by reduction with lithium aluminum hydride (after protection of the earbinol group) or by aqueous alkaline hydrolysis with lithium hydroxide to afford the corresponding carboxylic acid. In both cases, the chiral auxiliary reagent can be recovered. 

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

Reduction of aromatic carboxylic acids to alcohols can be achieved by hydrides and complex hydrides, e.g. lithium aluminum hydride 968], sodium aluminum hydride [55] and sodium bis 2-methoxyethoxy)aluminum hydride [544, 969, 970], and with borane (diborane) [976] prepared from sodium borohydride and boron trifluoride etherate [971, 977] or aluminum chloride [755, 975] in diglyme. Sodium borohydride alone does not reduce free carboxylic acids. Anthranilic acid was reduced to the corresponding alcohol by electroreduction in sulfuric acid at 20-30° in 69-78% yield [979],... 

The reduction of carboxylic acids or esters requires very powerful reducing agents such as lithium aluminum hydride (LiAlH,) or sodium (Na) metal. Aldehydes and ketones are easier to reduce, so they can use sodium borohy-dride (NaBH,j). Examples of these reductions are shown in Figure 3-13. 

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