Hydride as Nucleophile

Sodium borohydride, which was useful for aldehyde and ketone reduction, is less commonly used for other acid derivatives. While it will reduce acid chlorides or anhydrides to primary 

FIGURE 15.34 Reaction of lithium aluminum hydride with an ester. 

FIGURE 15.36 Reduction of esters to aldehydes using DIBAH. 

FIGURE 15.37 Reduction of acid chlorides to aldehydes using LI[AIH(0-f-Bu)3]. 

FIGURE 15.38 Reduction of acid derivatives by boroiaydride reagents. 

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Hydride as nucleophile lithium aluminium hydride and sodium borohydride reductions... 

Except in the formation of minor side products, the replacement of halogen by hydride as nucleophile is not observed. Halide exchange is also not a general process with [(haloarene)Cr(CO)3] species. 

Epoxides with an oxymethyl substituent (RO-CR2) usually react with nucleophiles at the non-oxymethyl-substituted carbon atom, because of the carbocation-destabilizing effect of this group. This is also observed for hydride as nucleophile, as illustrated by the examples in Scheme 4.63. 

This topic is covered in Sect. V.2.3.1. Therefore, only the role of carbonates will be emphasized here. The introduction of hydride as nucleophile produces the reduction of allylic carbonates, and therefore of allylic alcohols into alkenes. Tsuji and co-workers studied the synthetic possibilities very early,concluded that carbonates were better substrates than acetates, and observed that hydride attacks to the more substituted end of the allylic moiety. This is very useful to prepare the thermodynamically less stable 1-aUcenes (Scheme 26). A good hydride source is formate anion, generated from formic acid and a tertiary amine, that is, triethylamine in many examples reported by Tsuji, who also suggested tributylphosphine as auxiliary ligand. The intermediate rj -allylpalladium complex featuring formate as counteranion is postulated as intermediate in the reaction. Some stable formates have been isolated and shown to be ionic in the presence of enough ligand (Scheme 6). 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

An interesting variant in which nucleophilic aromatic substitution is carried out on the crown nucleus rather than using the crown as nucleophile was reported by Haines . In this approach, hexafluorobenzene was stirred in 1,2-dimethoxyethane at room temperature with pentaethylene glycol and sodium hydride. A double nucleophilic aromatic substitution occurred affording 2, 3, 4 ,5 -tetrafluorobenzo-15-crown-5 as an oil in 38% yield. The reaction is illustrated below. 

As with the reduction of carbonyl compounds discussed in the previous section, we ll defer a detailed treatment of the mechanism of Grignard reactions until Chapter 19. For the moment, it s sufficient to note that Grignard reagents act as nucleophilic carbon anions, or carbanions ( R ), and that the addition of a Grignard reagent to a carbonyl compound is analogous to the addition of hydride ion. The intermediate is an alkoxide ion, which is protonated by addition of F O"1 in a second step. 

When the hydride ion of lithium alanate is used as nucleophile, cyclohexa-2,4-dien-l-ol is obtained as a labile addition product which eliminates water on standing to give benzene.12 The reaction of an oxepin derivative that possesses a hexamethylene bridge across C3-C6 with sodium methoxide gives an addition product 5 in which the seven-membered heterocyclic system is retained.213 214... 

MetalIa-/3-diketonate complexes, such as 1, are conveniently prepared by reacting acylmetal carbonyl complexes with strong bases that can also react as nucleophiles, such as organolithium, Grignard, or boron hydride reagents [Eq. (1)]. These reactions can be followed by IR spectroscopy. 

Reactions of highly electron-rich organometalate salts (organocuprates, orga-noborates, Grignard reagents, etc.) and metal hydrides (trialkyltin hydride, triethylsilane, borohydrides, etc.) with cyano-substituted olefins, enones, ketones, carbocations, pyridinium cations, etc. are conventionally formulated as nucleophilic addition reactions. We illustrate the utility of donor/acceptor association and electron-transfer below. 

This reaction has been extensively used for the synthesis of polyfunctionalized piperidines with a wide range of nucleophiles selected and representative examples are collected in Table 15. From these results, hydrides, Grignard reagents, aluminium derivatives, allylsilane, as well as aromatics can be used as nucleophiles to give the corresponding C-8a functionalized compounds in good yields and, in most cases, excellent selectivities. 

Hydrostannation of alkenes and alkynes (Equation (14)) can involve nucleophilic (R3Sn H+), electrophilic (R3Sn+H ), or homolytic (R3Sm) tin, or the hydride as a metal complex (R3SnMH). 

Fig. 6) can activate hydrogen under mild conditions [219]. In contrast to transition metals, that act as electrophiles towards hydrogen, the (alkyl)(amino)carbenes mainly behave as nucleophiles initially creating a hydride like species, which then attacks the positively polarized carbene carbon atom. 

A number of complex metal hydrides such as lithium aluminium hydride (LiAlH4, abbreviated to LAH) and sodium borohydride (NaBHj) are able to deliver hydride in such a manner that it appears to act as a nucleophile. We shall look at the nature of these reagents later under the reactions of carbonyl compounds (see Section 7.5), where we shall see that the complex metal hydride never actually produces hydride as a nucleophile, but the aluminium hydride anion has the ability to effect transfer of hydride. Hydride itself, e.g. from sodium hydride, never acts as a nucleophile owing to its small size and high charge density it always acts as a base. Nevertheless, for the purposes of understanding the transformations. 

HYDRIDE AS A NUCLEOPHILE REDUCTION OF ALDEHYDES AND KETONES, LAH AND SODIUM BOROHYDRIDE... 

The carbonyl group of aldehydes and ketones may be reduced to an alcohol group by a nucleophilic addition reaction that appears to involve hydride as the nucleophile. The reduction of the carbonyl group may be interpreted as nucleophilic attack of hydride onto the carbonyl carbon, followed by abstraction of a proton from solvent, usually water. 

Whilst the complex metal hydride is conveniently regarded as a source of hydride, it never actually produces hydride as a nucleophile, and it is the aluminium hydride anion that is responsible for... 

HYDRIDE AS A NUCLEOPHILE REDUCHON OE CARBOXYLIC ACID DERIVAHVES... 

Hydride as a nucleophile reduction of carboxylic acid derivatives... 

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