Lithium Aluminum Hydride1

LiAlH4

[16853-85-3]  · AlH4Li  · Lithium Aluminum Hydride  · (MW 37.96)

(reducing agent for many functional groups;1 can hydroaluminate double and triple bonds;2 can function as a base3)

Alternate Name: LAH.

Physical Data: mp 125 °C; d 0.917 g cm-3.

Solubility: sol ether (35 g/100 mL; conc of more dil soln necessary); sol THF (13 g/100 mL); modestly sol other ethers; reacts violently with H2O and protic solvents.

Form Supplied in: colorless or gray solid; 0.5-1 M solution in diglyme, 1,2-dimethoxyethane, ether, or tetrahydrofuran; the LiAlH4.2THF complex is available as a 1 M solution in toluene.

Analysis of Reagent Purity: Metal Hydrides Technical Bulletin No. 401 describes an apparatus and methodology for assay by means of hydrogen evolution. See also Rickborn and Quartucci.39a

Handling, Storage, and Precautions: the dry solid and solutions are highly flammable and must be stored in the absence of moisture. Cans or bottles of LiAlH4 should be flushed with N2 and kept tightly sealed to preclude contact with oxygen and moisture. Lumps should be crushed only in a glove bag or dry box.

Functional Group Reductions.

The powerful hydride transfer properties of this reagent cause ready reaction to occur with aldehydes, ketones, esters, lactones, carboxylic acids, anhydrides, and epoxides to give alcohols, and with amides, iminium ions, nitriles, and aliphatic nitro compounds to give amines. Several methods of workup for these reductions are available. A strongly recommended option4 involves careful successive dropwise addition to the mixture containing n grams of LiAlH4 of n mL of H2O, n mL of 15% NaOH solution, and 3n mL of H2O. These conditions provide a dry granular inorganic precipitate that is easy to rinse and filter. More simply, solid Glauber's salt (Na2SO4.10H2O) can be added portionwise until the salts become white.5 In certain instances, an acidic workup (10% H2SO4) may prove advantageous because the inorganic salts become solubilized in the aqueous phase.6 Should water not be compatible with the product, the use of ethyl acetate is warranted since the ethanol that is liberated usually does not interfere with the isolation.4 Although the stoichiometry of LiAlH4 reactions is well established,1 excess amounts of the reagent are often employed (perhaps to make accommodation for the perceived presence of adventitious moisture). This practice is wasteful of reagent, complicates workup, and generally should be avoided.

The reduction of amides can be adjusted in order to deliver aldehydes. Acylpiperidides,7 N-methylanilides,8 aziridides,9 imidazolides,10 and N,O-dimethylhydroxylamides11 have proven especially serviceable. All of these processes generate products that liberate the aldehyde upon hydrolytic workup. The powerful reducing ability of LiAlH4 allows for its application in the context of other functional groups. Alkanes are often formed in good yield upon exposure of alkyl halides (I > Br > Cl; primary > secondary > tertiary)12 and tosylates13 to LiAlH4 in ethereal solvents. Chloride reduction is an SN2 process, while iodides enter principally into single electron transfer chemistry.14 Benzylic15 and allylic halides16 behave comparably, although the latter can react in an SN2 fashion as well (eq 1).17 Select aromatic halides can be reduced under forcing conditions (e.g. diglyme, 100 °C),18 but chemoselectivity as in eq 2 can often be achieved.19 Vinyl,20 bridgehead,20 and cyclopropyl halides (eqs 3 and 4)20,21 have all been reported to undergo reduction. The SET mechanism is also believed to operate in the latter context.22

LiAlH4 is normally unreactive toward ethers.1 Unsaturated acetals undergo reduction with double bond migration (SN2); in cyclic systems, the usual stereoelectronic factors often apply (eq 5).23 Orthoesters are amenable to attack, giving acetals in good yield (eq 6).24 The susceptibility of benzylic acetals to reduction can be enhanced by the co-addition of a Lewis acid (eq 7).25

When comparison is made between LiAlH4 and related reducing agents containing active Al-H and B-H bonds, LiAlH4 is seen to be the most broadly effective (Table 1).1h Its superior reducing power is also reflected in its speed of hydride transfer.

Hydroalumination Agent.

Ethylene has long been known to enter into addition with LiAlH4 when the two reagents are heated under pressure at 120-140 °C; lithium tetraethylaluminate results.2 Homogeneous hydrogenations of alkenes and alkynes to alkanes and alkenes, respectively, performed in THF or diglyme solutions under autoclave pressure, are well documented.26 Such reductions are greatly facilitated by the presence of a transition metal halide ranging from Ti to Ni.27 Replacement of the hydrolytic workup by the addition of appropriate halides constitutes a useful means for chain extension (eq 8).28 1-Chloro-1-alkynes are notably reactive toward LiAlH4, addition occurring regio- and stereoselectively to give alanates that can be quenched directly (MeOH) or converted into mixed 1,1-dihaloalkenes (eq 9).29

A pronounced positive effect on the ease of reduction of C=C and C&tbond;C bonds manifests itself when a neighboring hydroxyl group is present. In such cases, LiAlH4 is used alone because reduction is preceded by formation of an alkoxyhydridoaluminate capable of facilitating hydride delivery (eqs 10-12).30-32 The regio- and stereoselectivities of these reactions, where applicable, appear to be quite sensitive to the substrate structure and solvent.33 Generally, the use of THF or dioxane results in exclusive anti addition. When ether is used, almost equivalent amounts of syn and anti products can result. Considerable attention has been accorded to synthetic applications of the alanate intermediates produced upon reduction of propargyl alcohols in this way. Simple heating occasions elimination of a d-leaving group to generate homoallylic34 and a-allenic alcohols (eqs 13 and 14).35 Other variants of this chemistry have been reported.36 The addition at -78 °C of solid iodine to alanates formed in this way greatly accelerates the elimination (eq 15).37 Solutions of iodine in THF give rise instead to vinyl iodides.38

Epoxide Cleavage and Aziridine Ring Formation.

Epoxides are reductively cleaved in the presence of LiAlH4 with attack generally occurring at the less substituted carbon.1g 1,2-Epoxycyclohexanes exhibit a strong preference for axial attack (eqs 16 and 17).39 In general, cis isomers are more reactive than their trans counterparts; ring size effects are also seen and these conform to the degree of steric inhibition to backside attack of the C-O bond.40 Vinyl epoxides often suffer ring opening by means of the SN mechanism (eq 18).41

Two types of oximes undergo hydride reduction with ring closure to give aziridines. These are ketoximes that carry an a- or b-aryl ring and aldoximes substituted with an aromatic group at the b-carbon (eqs 19 and 20).42

Use as a Base.

Both 1,2- and 1,3-diol monosulfonate esters react with LiAlH4 functioning initially as a base and subsequently in a reducing capacity (eqs 21 and 22).3,43

Reduction of Sulfur Compounds.

Sulfur compounds react differently with LiAlH4 depending on the mode of covalent attachment of the hetero atom and its oxidation state. Reductive desulfurization is not often encountered.44 Arylthioalkynes undergo stereoselective trans reduction (eq 23)45 and a-oxoketene dithioacetals are transformed into fully saturated anti alcohols under reflux conditions (eq 24).46 While LiAlH4 catalyzes the fragmentation of sulfolenes to 1,3-dienes,47 the lithium salts of sulfolanes are smoothly ring contracted when heated with the hydride in dioxane (eq 25).48

Stereoselective Reductions.

The reduction of 4-t-butylcyclohexanone and (1) by LiAlH4 occurs from the axial direction to the extent of 92%49 and 85%,50 respectively. When a polymethylene chain is affixed diaxially as in (2), the equatorial trajectory becomes kinetically dominant (93%).50 Thus, although electronic factors may be an important determinant of p-facial selectivity,51 steric demands within the ketone cannot be ignored. The stereochemical characteristics of many ketone reductions have been examined. For acyclic systems, the Felkin-Ahn model52 has been widely touted as an important predictive tool.53 Cram's chelation transition state proposal54 is a useful interpretative guide for ketones substituted at Ca with a polar group. Cieplak's explanation55 for the stereochemical course of nucleophilic additions to cyclic ketones has received considerable scrutiny.56

Useful levels of diastereoselectivity can be realized upon reduction of selected acyclic ketones having a proximate chiral center.57 The contrasting results in eq 26 stem from the existence of a chelated intermediate when the benzyloxy group is present and its deterrence when a large silyl protecting group is present. In the latter situation, an open transition state is involved.58,59 In eq 27, LiAlH4 alone shows no stereoselectivity, but the co-addition of Lithium Iodide gives rise to a syn-selective reducing agent as a consequence of the intervention of a Li+-containing six-membered chelate.60

The reduction of amino acids to 1,2-amino alcohols can be conveniently effected with LiAlH4 in refluxing THF.61 The higher homologous 1,3-amino alcohols have been made available starting with isoxazolines, the process being syn selective (eq 28).62,63 The syn and anti O-benzyloximes of b-hydroxy ketones are reduced with good syn and anti stereoselectivity, respectively.64 However, when NaOMe or KOMe is also added, high syn stereoselectivity is observed with both isomers (eq 29).65

Addition of Chiral Ligands.

If a chiral adjuvant is used to achieve asymmetric induction, it should preferentially be inexpensive, easily removed, efficiently recovered, and capable of inducing high stereoselectivity.53 Of these, 1,3-oxathianes based on (+)-camphor66 or (+)-pulegone,67 and proline-derived 1,3-diamines,68 have been accorded the greatest attention.

Extensive attempts to modify LiAlH4 with chiral ligands in order to achieve the consistent and efficient asymmetric reduction of prochiral ketones has provided very few all-purpose reagents.1f,69 Many optically active alcohols, amines, and amino alcohols have been evaluated. One of the more venerable of these reagents is that derived from DARVON alcohol.70 The use of freshly prepared solutions normally accomplishes reasonably enantioselective conversion to alcohols.71 As the reagent ages, its reduction stereoselectivity reverses.70 This phenomenon is neither understood nor entirely reliable, and therefore recourse to the enantiomeric reagent72 (from NOVRAD alcohol) is recommended.73 The highest level of enantiofacial discrimination is usually realized with LiAlH4 complexes prepared from equimolar amounts of (S)-(-)- or (R)-(+)-2,2-dihydroxy-1,1-binaphthyl and ethanol.74 Often, optically pure alcohols result, irrespective of whether the ketones are aromatic,74 alkenic,75 or alkynic in type.76 A useful rule of thumb is that (S)-BINAL-H generally provides (S)-carbinols and (R)-BINAL-H the (R)-antipodes when ketones of the type Runsat-C(O)-Rsat are involved (eq 30).74

For a more detailed discussion of asymmetric induction by this means, see also the following entries that deal specifically with LiAlH4/additive combinations.

Related Reagents.

Lithium Aluminum Hydride-(2,2-Bipyridyl)(1,5-cyclooctadiene)nickel; Lithium Aluminum Hydride-Bis(cyclopentadienyl)nickel; Lithium Aluminum Hydride-Boron Trifluoride Etherate; Lithium Aluminum Hydride-Cerium(III) Chloride; Lithium Aluminum Hydride-2,2-Dihydroxy-1,1-binaphthyl; Lithium Aluminum Hydride-Chromium(III) Chloride; Lithium Aluminum Hydride-Cobalt(II) Chloride; Lithium Aluminum Hydride-Copper(I) Iodide; Lithium Aluminum Hydride-Diphosphorus Tetraiodide; Lithium Aluminum Hydride-Nickel(II) Chloride; Lithium Aluminum Hydride-Titanium(IV) Chloride; Titanium(III) Chloride-Lithium Aluminum Hydride.


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Leo A. Paquette

The Ohio State University, Columbus, OH, USA



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