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Specific Solvent Issues with Amide Reduction

Traditional hydride reagents –LiAlH4, Boranes, Sodium bis(2-methoxyethoxy) aluminum hydride

(Vitride / Red-Al) etc. are often deployed in ethereal solvents.

This is for a number of reasons:

  • Solubility of ionic reagents.
  • Stabilisation and reactivity modification by the solvent acting as a ligand.
  • Compatibility with strong hydride donors
  • Historically, LiAlH4 has often been used in diethyl ether due to its unusually high solubility in this solvent

    • See table below and references. Owing to the high operational safety hazard, diethyl ether should not be used and substituted with a safer solvent.

    Solubility of LiAlH4 (mol/L)
    Temperature (°C)
    Solvent 0 25 50 75 100
    Diethyl ether 5.92
    THF 2.96
    Monoglyme 1.29 1.80 2.57 3.09 3.34
    Diglyme 0.26 1.29 1.54 2.06 2.06
    Triglyme 0.56 0.77 1.29 1.80 2.06
    Tetraglyme 0.77 1.54 2.06 2.06 1.54
    Dioxane 0.03
    Dibutyl ether 0.56

    Solubility of lithium aluminum hydride and lithium borohydride in diethyl ether

    Care should also be exercised in avoiding excessive heat since these metal hydride reagents can decompose liberating Hydrogen. Higher temperatures can result in violent and exothermic  reaction with the solvent. 2M BH3 in THF is hazard class 4.1 self reactive hazardous material with a self-accelerating decomposition temperature (SADT) of 40 °C

    See references below on incident relating to explosion of  400 l cylinder of 2M BH3 in THF

    Org. Process Res. Dev. 2003, 7, 1029-1033  

    C&E News July 1, 2002 Volume 80, Number 26

    Several ethereal solvents used in conjunction with NaBH4 to generate BH3 or BH3 complexes in situ are candidates for the ECHA Substances of very high concern list (SVHC list) due to human repotoxicity effects and their use maybe restricted in the EU.

    ECHA data for triglyme

    ECHA data for diglyme

    Sodium bis(2-methoxyethoxy)aluminumhydride will liberate 2 moles of 2-methoxyethanol on hydrolysis. This material is also of concern due to human reprotoxicity effects.

    ECHA data for 2-methoxyethanol

    Metal hydrides in the presence of chlorinated solvents can be dangerously unstable—incompatible-materials

    Increasingly, LiAlH4 and borane reductions are being reported in the greener ether solvents CPME and 2-methyl THF

    Org. Process Res. Dev. 2007, 11, 251-258 Cyclopentyl Methyl Ether as a New and Alternative Process Solvent

    Org. Process Res. Dev. 2007, 11, 156–159 Solvent Applications of 2-Methyltetrahydrofuran in Organometallic.