Nucleophilic addition of hydride

Figure 19.7 Mechanism of carbonyl-group reduction by nucleophilic addition of "hydride ion" from NaBH4 or LiAIH4.

Reduction Conversion of Nitriles into Amines Reduction of a nitrile with LiAIH4 gives a primary amine, RNH . The reaction occurs by nucleophilic addition of hydride ion to the polar C=N bond, yielding an imine anion, which still contains a C=N bond and therefore undergoes a second nucleophilic addition of hydride to give a dianion. Both monoanion and dianion intermediates are undoubtedly stabilized by Lewis acid-base complexafion to an aluminum species, facilitating the second addition that would otherwise be difficult Protonation of the dianion by addition of water in a subsequent step gives the amine. 

Amide reduction occurs by nucleophilic addition of hydride ion to the amicle carbonyl group, followed by expulsion of the oxygen atom as an alumi-nate anion leaving group to give an iminium ion intermediate. The intermediate iminium ion is then further reduced by JL1AIH4 to yield the amine. 

Reductive animations also occur in various biological pathways, fn the biosynthesis of the amino acid proline, for instance, glutamate 5-semjaldehyde undergoes internal imine formation to give 1-pyrrolinium 5-carboxylate, which is then reduced by nucleophilic addition of hydride ion to the C=N bond. 

The reverse reaction, i.e. reduction, is also indicated in the scheme, and may be compared with the chemical reduction process using complex metal hydrides, e.g. LiAlPLj or NaBH4, namely nucleophilic addition of hydride and subsequent protonation (see Section 7.5). The reduced forms NADH and NADPH are conveniently regarded as hydride-donating reducing agents (see Box 7.6). We also noted that there were stereochemical features associated with these coenzymes (see Box 3.14). During a reduction... 

SGF-LCGO calculations for the nucleophilic addition of hydride ion to formaldehyde to yield methanolate anion (H + CH2 = 0 CHjO ) have been carried out (83, 84). Interestingly, the calculated reaction path for this reaction shows striking similarities to that derived from structural correlations for amine addition to a ketone function. 

Super Hydride is one of the most powerful nucleophilic reducing agents available, capable of reducing many functional groups. It is also highly selective. The exocyclic double bond in aryl-substituted fulvenes has an increased polarity, due to the inductive effects of their respective aryl groups. This increased polarity allows for selective nucleophilic attack at this double bond and not at the diene component of the fulvenes. Other examples of the nucleophilic addition of hydrides to substituted fulvenes (albeit with alkyl or unsubstituted phenyl group functionality)... 

The reaction occurs by nucleophilic addition of hydride ion to the polar bond, yieldiiig an itnine anion that undergoes further addition of a secui ec uivalent of hydride. Ifl however, a leas powerful reducing agent such DIBAH is used, the second addition of hydride does not occur, and tlie iin4 intermediate ran be hydrolyzed by addition of water to yield an aldehyde. 

The reduction of carbonyl compounds with metal hydride reagents can be viewed as nucleophilic addition of hydride to the carbonyl group. Addition of a hydride anion to an aldehyde or ketone produces an alkoxide anion, which on protonation gives the corresponding alcohol. Aldehydes give 1°-alcohols and ketone gives 2°-alcohols. 

We begin our study of nucleophilic additions to aldehydes and ketones by briefly reviewing nucleophilic addition of hydride and carbanions, two reactions examined in Sections 20.4 and 20.10, respectively. 

The mechanism of both reactions involves nucleophilic addition of hydride (H ) to the polarized C - N triple bond. With LiAlHj, two equivalents of hydride are sequentially added to yield a dianion (Steps [l]-[2]), which is then protonated with HgO to form the amine in Step [3], as shown in Mechanism 22.12. 

Alternatively, for A -monosubstituted thioamides, methods based on nucleophilic addition of hydride, carbanions, or cyanide to isothiocyanates are available, and, quite often, thionation of the corresponding amides provides a convenient route to thioamides (c/. Volume 6, Chapters 4.1 and 4.3). ... 

D. Basavaiah and co-workers achieved the simple and convenient stereoselective synthesis of ( )-a-methylcinnamic acids via the nucleophilic addition of hydride ion from sodium borohydride to acetates of Bayiis-Hillman adducts (methyl 3-acetoxy-3-aryl-2-methylenepropanoates), followed by hydrolysis and crystaliization. The potential of this methodology was demonstrated in the synthesis of ( )-p-(myristyloxy)-a-methylcinnamic acid, which is an active hypolipidemic agent. 

Br, or I) (equation 1). Another method relies on alkylation of a-hydroxy or a-alkoxy carbonyl compounds. The induction of diastereoselectivty, in these cases, is achieved through the use of chiral auxiliaries and other stereodirecting groups (equation 2). The third method frequently utilizes the nucleophilic addition of hydride or other carbanions to a-dicarbonyl compounds (equation 3). In addition to being laborious, nonoxidative methods are limited to the synthesis of acyclic compounds, which greatly reduces the magnitude of their synthetic practicality. 

The ketone product is readily reduced by LiAIH4, by nucleophilic addition of hydride anion (H ), to give an alkoxide product. 

Reduction of the nitrile group proceeds by nucleophilic addition of hydride twice to give an amine. 

Nucleophilic addition of hydride ion to the carbonyl carbon gives a tetrahedral carbonyl addition intermediate. The hydride ion is not free but is donated by the AlH,j ion. 

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