Reduction of nitriles to primary amines with LiAlH4

by James

Description: Lithium aluminum hydride [but NOT sodium borohydride (NaBH4)] can reduce nitriles to primary amines.
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Notes:

The purpose of acid at the end is to protonate the nitrogen in order to give the amine.

Note that 2 or more equivalents of LiAlH4 is best for this reaction.

Examples:

Notes: Note that the last example is a cyanohydrin, which also works in this reaction.

Mechanism:

Addition of hydride ion (H–) from LiAlH4 to the carbon of the nitrile in a 1,2-addition (Step 1, arrows A and B) followed by addition of a second equivalent of hydride (Step 2, arrows C and D) gives an amine anion. When acid is added, the nitrogen is protonated twice to give the neutral amine.

Notes: The choice of Cl as the counter-ion for H3O(+) here is completely arbitrary – it’s just a spectator ion, anyway. Note that it could also be reasonable to use an equivalent of AlH3 formed after Step 1 as the reducing agent in Step 2.

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{ 4 comments… read them below or add one }

Kapil

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Matthew Granger

For step 2. Instead of N- getting a second negative charge N (2-), would it first protonate itself once? and then repeat from there until it left?

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James

Hey Matt – although N is drawn with a second negative charge in practice it will be bound to aluminum [an excellent Lewis acid], and the Al-N bond will be quite strong so it’s not as “naked” as it appears. There aren’t really any proton sources present to protonate the nitrogen at this stage until workup.

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Matthew Granger

Yeah, that makes sense, basically the electron density of N is being donated to Al, resulting in less anionic nature as observed.
Thanks James!

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