Carboxylic acids with LiAlH

The key in each part is to convert the carboxylic acid to an amide and then to reduce the amide with LiAlH. The amide can be prepared by treating the carboxylic acid with SOCI2 to give the acid chloride (Section 17.8) and then treating the acid chloride with an amine (Section 18.6A). Alternatively the carboxylic acid can be converted to an ethyl ester by Fischer esterification, and the ester can then be treated with an amine to give the amide. Solution (a) uses the acid chloride route, and solution (b) uses the ester route. 

The conversion of carboxylic acid derivatives (halides, esters and lactones, tertiary amides and lactams, nitriles) into aldehydes can be achieved with bulky aluminum hydrides (e.g. DIBAL = diisobutylaluminum hydride, lithium trialkoxyalanates). Simple addition of three equivalents of an alcohol to LiAlH, in THF solution produces those deactivated and selective reagents, e.g. lithium triisopropoxyalanate, LiAlH(OPr )j (J. Malek, 1972). 

Conversion of Amides into Amines Reduction Like other carboxylic acid derivatives, amides can be reduced by LiAlH.4. The product of the reduction, however, is an amine rather than an alcohol. The net effect of an amide reduction reaction is thus the conversion of the amide carbonyl group into a methylene group (C=0 —> CTbV This kind of reaction is specific for amides and does not occur with other carboxylic acid derivatives. 

The final step is to convert the carboxylic acid into a primary alcohol by heating it with lithium aluminium hydride (LiAlH ) dissolved in ether (ethoxyethane). This is a reduction reaction and delivers the target molecule, propan-l-ol. 

Carboxylic acids, acid chlorides, acid anhydrides and esters get reduced to primary alcohols when treated with lithium aluminium hydride (LiAlH) (Fig.M). The reaction involves nucleophilic substitution by a hydride ion to give an intermediate aldehyde. This cannot be isolated since the aldehyde immediately undergoes a nucleophilic addition reaction with another hydride ion (Fig.N). The detailed mechanism is as shown in fig.O. 

Selective reduction of functional groups can be achieved by chemical modification of the LiALH4 for example, lithium tri(t-butoxy)aluminium hydride [LiAIH(t-OBu)3] is a more selective reagent, and reduces aldehydes and ketones, but slowly reduces esters and epoxides. Nitriles and nitro groups are not reduced by this reagent. Carboxylic acids can be converted into the aldehyde via acid chloride with lithium tri(tert-butoxy) aluminium hydride at a low temperature (—78°C). The nitro compounds are not reduced under this condition. Thus, selective reduction of 3,5-dinitrobenzoic acid (6.45) to 3,5-dinitrobenzaldehyde (6.47) can be achieved in two steps. First, 6.45 is converted into 3,5-dinitrobenzoyl chloride (6.46) and then LiAlH(t-OBu)3 reduction of 6.46 gives 6.47. 

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. 

The rationale for this reaction is similar to that given earlier for the reduction of acids by LiAlH. The first step is reaction with the proton of the carboxylic... 

Carboxylic acid on treatment with LiAlH gives rise to a primary alcohol. 

Amides differ from carboxylic acids and other acid derivatives in their reaction with LiAlH Instead of forming primary alcohols, amides are reduced to amines (Fig.P). The mechanism (Fig.Q) involves addition of the hydride ion to form an intermediate that is converted to an organoaluminium intermediate. The difference in this mechanism is the intervention of the nitrogen s lone pair of electrons. These are fed into the electrophilic centre to eliminate the oxygen that is then followed by the second hydride addition. 

Lithium aluminum hydride, LiAlH (LAH), reduces a carboxylic acid to a primary alcohol in excellent yield, although heating is required. LAH is usually dissolved in diethyl ether or tetrahydrofuran (THF). When carboiylic acids react with LiAlH,, the initial product is a tetraalkoxy aluminate ion, which is then treated with water to give the primary alcohol and lithium and aluminum hydroxides. These hydroxides are insoluble in diethyl ether and THF and are removed by filtration. Evaporation of the solvent then yields the primary alcohol. 

For example, reduction of acid chlorides (RCOCl), prepared from carboxylic acids by reaction between the acid and, for example, thionyl chloride (vide infra), with hydrogen over a barium sulfate (BaS04) poisoned palladium (Pd) catalyst (the Rosenmund reduction), can often be used to produce the corresponding aldehyde (RCHO). The same product can more easily be obtained from the same starting material by using commercially available lithium aluminum tri-r-butoxy hydride (LiAlH[OC(CH3)3]3) in an ether solvent,such as bis(2-methoxyethyl)ether [diglyme, (CH30CH2CH2)20], at -78°C (Scheme 9.106). 

Carboxylic acids can be reduced to their corresponding primary alcohol by using the reducing agent lithium tetrahydridoaluminate, LiAlH, in dry ether at room temperature. Dry ether is used because LiAlH reacts violently with water. 

The RCN molecule can be either hydrolysed to make a carboxylic acid (by refluxing with dilute hydrochloric acid) or reduced to make an amine (by adding LiAlH in dry ether). 

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