Hydride Reduction of a Carbonyl Group

Sodium borohydride and lithium aluminum hydride reduce ketones and aldehydes to alcohols. 

Reaction 1 Nucleophilic attack by hydride ion forms an alkoxide ion. 

Reaction 2 After the first reaction is complete, water or dilute acid is added to protonate the alkoxide. 

---

Hydroboration-reduction of enones.2 Hydride reduction of a carbonyl group can be used to induce asymmetric intramolecular hydroboration of a double bond via a cyclic transition state. Thus reaction of the enone 1 with thexylborane (1 equiv.) followed by oxidation provides the 1,5-diol 2 with high 1,4-syn selectivity. A similar reaction with the homologous enone provides a 1,6-diol with modest 1.5-syn selectivity (syn anti = 6.6 1). 

Mechanism 10-2 Hydride Reduction of a Carbonyl Group 454 Summary Reactions of LiAIH4 and NaBH4 455 Summary Alcohol Syntheses by Nucleophilic Additions to Carbonyl Groups 457 10-12 Thiols (Mercaptans) 458 EssentialTerms 461 Study Problems 462... 

Hydride Reduction of a Carbonyl Group 454 Reaction of a Tertiary Alcohol with HBr(S[ 1) 480 Reaction of a Primary Alcohol with HBr (SN2) 480 Reaction of Alcohols with PBr3 485 (Review) Acid-Catalyzed Dehydration of an Alcohol 487 The Pinacol Rearrangement 495 Cleavage of an Ether by HBr or HI 639 Acid-Catalyzed Opening of Epoxides in Water 649 Acid-Catalyzed Opening of an Epoxide in an Alcohol Solution 650... 

Stereospecificity has been observed in the metal hydride reduction of a carbonyl group situated a to a complexed ring, but included in a rigid structure [e.g., indanone (LI)]. Whatever the reducing agent used, only the endo isomer LII is obtained. 

Neither sodium borohydride nor lithium aluminum hydride reduces isolated carbon-carbon double bonds This makes possible the selective reduction of a carbonyl group m a molecule that contains both carbon-carbon and carbon-oxygen double bonds... 

In the reduction of a carbonyl group, there is an initial transfer of a hydride ion by an SN2 mechanism when the complex (1) is formed. Since it has still three more hydrogen atoms, it reacts with three more molecules of ketone to give the alkoxide (2) Hydrolysis of the latter gives secondary alcohol, along with aluminium and lithium hydroxides. 

In a bifunctional compound, if a reagent reacts with one functional group preferentially, even though the other is apparently susceptible to the reaction conditions, the reaction is said to be chemoselective. Two illustrative examples are the reduction of a carbonyl group in the presence of a cyano, nitro or alkoxycarbonyl group (Section 5.4.1, p. 519 see also Metal hydrides, Section 4.2.49, p. 445) and the acylation of an aromatic amino group in the presence of a phenolic group (Section 6.9.3, p. 984). 

The reduction of a carbonyl group to an olefin has been accomplished by the Shapiro modification5 of the Bamford-Stevens reaction and by the hydride reduction of the corresponding enol ether,6 enol acetate,7 or en-amine.8 The nickel reduction of the thioketal has also been used successfully.9... 

Stork and Danheiser have developed a highly useful procedure for the synthesis of 4-alkylcyclohex-2-enones, which involves a -alkylations of cross-conjugated lithium dienolates of 3-alkoxycyclohex-2-enones, followed by metal hydride reduction of the carbonyl group and hydrolysis (Scheme 30). Numerous applications of this procedure have been reported.Two different alkyl groups may be introduced at the 6-position of a cyclohex-2-enone derivative without difficulty. While dialkylation is generally not a problem in alkylations of cross-conjugated dienolates of cyclohex-2-enones, it was observed when relatively acidic 3-chlorocyclohex-2-enones were employed. ... 

In the Eqs. 58 and 59, an oxy anion provides the necessary electronic push for the 1,4-elimination to take place smoothly. In Eq. 58, this oxy anion was generated in situ by hydride reduction of the carbonyl group [27]. The in situ oxy anion generation in Eq. 59 was achieved by the cleavage of the ester group on reaction with an alkoxide ion in a protocol that is typical of transesterification [28]. 

The hydride anion (H ) behaves as a nucleophile in the reduction of a carbonyl group and binds to the positively charged carbon atom. The remaining AIH3 is a Lewis acid which, as an electron acceptor, attacks the oxygen. After hydrolysis and release of aluminum hydroxide, the reaction ends with the formation of an alcohol, in this case propanol (see the following scheme). 

The key step in the reduction of a carbonyl group by sodium borohydride is the transfer of a hydride ion ( H ) from boron to the carbon atom of the polarized carbonyl group ... 

The reduction of a carbonyl group with LAH or NaBH4 is not a reversible process, because hydride does not function as a leaving group. Notice that the mechanism above employs oneway arrows (rather than equilibrium arrows) to signify that the reverse process is insignificant. 

The reduction of a carbonyl group with LAH or NaBH4 is not a reversible process, because hydride does not function as a leaving group. 

When hthium aluminum hydride is used to reduce carbonyl compounds, an ether, such as diethyl ether, (CH CH ljO, is used as the solvent. The reduction of a carbonyl group by lithium aluminum hydride occurs by transfer of a hydride anion from A1H to the carbonyl carbon atom. The carbonyl oxygen atom forms an alkoxyaluminate salt. 

Lithium aluminium hydride LiAlH is a useful and conveuient reagent for the selective reduction of the carbonyl group and of various other polar functional groups. It is obtained by treatment of finely powdered lithium hydride with an ethereal solution of anhydrous aluminium chloride ... 

Reduction of an azide a nitrile or a nitro compound furnishes a primary amine A method that provides access to primary secondary or tertiary amines is reduction of the carbonyl group of an amide by lithium aluminum hydride... 

Enantiomerically pure /J-keto sulfoxides are prepared easily via condensation of a-lithiosulfinyl carbanions with esters. Reduction of the carbonyl group in such /J-keto sulfoxides leads to diastereomeric /J-hydroxysulfoxides. The major recent advance in this area has been the discovery that non-chelating hydride donors (e.g., diisobutylaluminium hydride, DIBAL) tend to form one /J-hydroxysulfoxide while chelating hydride donors [e.g., lithium aluminium hydride (LAH), or DIBAL in the presence of divalent zinc ions] tend to produce the diastereomeric /J-hydroxysulfoxide. The level of diastereoselectivity is often very high. For example, enantiomerically pure /J-ketosulfoxide 32 is reduced by LAH in diethyl ether to give mainly the (RR)-diastereomer whereas DIBAL produces exclusively the (.S R)-diastereomer (equation 30)53-69. A second example is shown in... 

An important contribution of the resonance form b requires the donation of electron density form the metal to the dienyl ligand [M(dM) -> C(pn-) contribution], The presence of a carbonyl group (a strong TT-acceptor ligand) trans to the dienyl reduces the M(dM) - C(ptt) contribution and, therefore, the nucleo-philicity of the unsaturated ii -carbon ligand. Then the nucleophilic center of the molecule is not the alkenyl ligand but the metallic center, and the protonation at the metal leads to the olefin via reductive elimination from a hydride-dienyl intermediate.24... 

---