Reagent of the month: Lithium Aluminium hydride

One might think that this hard-hitting, students best friend (it will reduce just about anything given the right conditions and is the go-to reducing agent for exam questions involving a reduction) has little more to offer to the practising chemist. However, a recent paper by Harder etal (Angew Chem Int Ed. 2018, 57(24), 7156) demonstrates its use as a catalyst for hydrogenation of imines.

Developed in the 40’s and rapidly commercialized, LiAlH4 remains a bulk reagent for large scale industrial reduction.[1] LiAlH4 is a stable crystalline solid, soluble in ether solvents in which it forms an aluminium complex (solubility Et2O 39g/100ml, THF 15g/100ml, THF/toluene (70/30) 17g/100ml) and able to reduce most polar functional groups (acids, amides, ester and nitriles).[2] This complex has higher solubility in toluene than the free powder and toluene is a favoured reaction solvent at scale due to ease of handling and work-up. Commercially, LiAlH4 is supplied in ready-to use ethereal solutions, or in solid form in solvent soluble bags or pellets for ease of handling.  Both the powder and solutions react extremely violently with water liberating hydrogen gas, necessitating strict engineering and safety controls in large scale industrial settings and vigilance on the part of the chemist in the lab.

 One drawback with its use industrially is the generation of copious amounts of lithium and aluminium salts that can cause problems during work-up and have a significant environmental impact. In reductions with LiAlH4 25.4Kg of LiAl(OH)4 are obtained per kmol H after hydrolysis.2


Unlike classical imine reduction with LiAlH4, which requires stochiometric amounts of reagent, Harder describes the use of catalytic quantities of LiAlH4 (2.5mol%) under a hydrogen atmosphere using surprisingly mild conditions (85°C, 1 bar H2, Figure). The reaction gives higher conversion in the absence of solvent, however THF and benzene could still be employed. Though the substrate scope is somewhat limited, the concept of a catalytic process for the hydrogenation of other functional groups (particularly amides), avoiding the generation of significant waste streams is attractive.

Historical attempts to reduce other functional groups have, however, shown limited utility.[1]

Mechanistically the LiAlH4 is thought to act a s a precatalyst- the actual species generated in the catalytic cycle is proposed to be the double insertion product (LiAlH2[N]2). This is underpinned by DFT calculations and crystal structures of isolated imine complexes.


[1] Magano etal Org. Pros. Res. Dev. 2012, 16, 1156

[2] Rittmeyer Chmica Oggi / chemistry today October 1995

[3] Slaugh etal Tetrahedron 1966, 22, 1741