Nucleophilic substitution hydride sources

The Ji-electron cloud above and below the plane of the benzene ring is a source of electron density and confers nucleophilic properties on the system. Thus, reagents that are deficient in electron density, electrophiles, are likely to attack, whilst electron-rich nucleophiles should be repelled and therefore be unlikely to react. Furthermore, in electrophilic substitution the leaving group is a proton, H", but in nucleophilic substitution it is a hydride ion, H the former process is energetically more favourable. In fact, nucleophilic aromatic suhstitution is not common, but it does occur in certain circumstances. 

Reduction of these C X a bonds is another example of nucleophilic substitution, in which LiAlHi serves as a source of a hydride nucleophile (H ). Because H" is a strong nucleophile, the reaction follows an Sn2 mechanism, illustrated for the one-step reduction of an alkyl halide in Mechanism 12.3. 

The rate-determining step in the ionic hydrogenation reaction of carbon-carbon double bonds involves protonation of the C==C to form a carbocation intermediate, followed by the rapid abstraction of hydride from the hydride source (equation 45). ° There is a very sensitive balance between several factors in order for this reaction to be successful. The proton source must be sufficiently acidic to protonate the C—C to form the intermediate carbocation, yet not so acidic or electrophilic as to react with the hydride source to produce hydrogen. In addition, the carbocation must be sufficiently electrophilic to abstract the hydride from the hydride source, yet not react with any other nucleophile source present, i.e. the conjugate anion of the proton source. This balance is accomplished by the use of trifluoroacetic acid as the proton source, and an alkylsilane as the hydride source. The alkene must be capable of undergoing protonation by trifluoroacetic acid, which effectively limits the reaction to those alkenes capable of forming a tertiary or aryl-substituted carbocation. This essentially limits the application of this reaction to the reduction of tri- and tetra-substituted alkenes, and aryl-substituted alkenes. 

With silyl-substituted oxiranes, dibal-H favors the primary alcohol and Bu 3A1H favors the secondary alcohol. These observations have been interpreted in terms of the timing of the hydride transfer to one of the oxirane carbons. dibal-H, which exists as a Lewis complex in donor media (R3N-A1H(Bu )2, or R20-A1H(Bu )2) acts as a nucleophilic hydride source, which preferentially attacks the least-hindered carbon. With Bu 3A1, complexation with the oxirane oxygen precedes isobutene elimination and the generation of the Al—H bond. A considerable carbocation character is acquired in the transition state, hence formation of the primary alcohol is favored. It is worthy of note that trialkylstannyl-substituted oxiranes are reduced with Red-Al invariably at the oxirane... 

Unsymmetrical ir-allyl-Pd complexes usually suffer attack of the hydride nucleophile at the less substituted position in an SN2-type reaction. However, the site selectivity of the process is controlled by steric and/or electronic effects. The reaction is strongly dependent on the structural features of the substrate and the reaction conditions. Opposite site selectivity is observed when the reduction occurs at the sterically more hindered position via a cationic intermediate (SN1-type). Very potent nucleophilic hydride sources, such as LiBHEt3 or LiAlH4, may rapidly attack intermediate it-ally 1 complexes at the less hindered terminal position to give the more substituted alkene, while less effective hydride-transfer reagents (NaBH3CN, NaBH4) attack the it-allyl systems at the site best able... 

Coordination of alkenes by [)j -CpFe(CO)2] activates alkenes toward nucleophilic substitution. For cationic alkene complexes )j -CpFe(CO)(PPh3)H can serve as a source of nucleophilic hydride. Thus, the transformations ... 

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). 

Apart from the common heteroatom-derived nucleophiles described, cleavage with other nucleophiles is also possible. For example, reductive cleavage with hydride sources is possible. For ester-linked substrates, Kurth et al. reported an example in which substituted propane-1,3-diols were prepared (Table 1.2, Entry 11). In related work, Chandrasekhar et al. prepared tertiary alcohols by treating an ester-linked substrate with excess Grignard reagent (Table 1.2, Entry 12). If, however, it is desirable to prepare the carbonyl derivative (and not reduce all the way to the corresponding alcohol), then Weinreb-type linker units can be used (Table 1.2, Entries 13 and 14). Treatment of substrates attached via such linkers... 

Tetraalkylborates are mild and selective alkylation reagents [186, 187], and they are commonly considered as sources of nucleophilic alkyl groups (R ) just as borohy-drides are depicted as hydride (H ) sources. However, since organoborates represent excellent electron donors (see Table 5, Section 2.2.1), the question arises as to what role electron donor-acceptor interactions play in the nucleophilic alkyl transfer. Phenyl- and alkyl-substituted borate ions form highly colored charge-transfer salts with a variety of cationic pyridinium acceptors [65], which represent ideal substrates to probe the methyl-transfer mechanisms. Most pyridinium borate salts are quite stable in crystalline form (see for example Figure 5C), but decompose rapidly when dissolved in tetrahydrofuran to yield methylated hydropyridines (Eq. 65). 

Of practical importance are the reactions of the quaternary salts of pyridine 1-oxides with aqueous potassium cyanide. The 1-methoxypyridinium methosulphates have usually been used, and with aqueous potassium cyanide, 2- and 4-cyanopyridine result [Table 5.25), the 2-position being somewhat favoured. A 3-substituent usually, but not always, causes 2-substitution to predominate over 6-substitution. The quaternary function is eliminated as an alcohol its presence probably determines the preference for 2- over 4-substitution, and its ready elimination makes the reaction a practicable source of cyanopyridines, in contrast to the case of other quaternary pyridinium salts (see above) with which reaction stops at the addition stage. These reactions are nucleophilic replacements not of hydride but of alkoxyl ... 

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