Addition of Grignard reagents to nitriles to give ketones (after hydrolysis)

by James

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Description: Grignard reagents will add once to nitriles to form imines. The imines can be treated with aqueous acid to give ketones.

Notes:

  • The purpose of  the second step is to convert the intermediate imine into a ketone.
  • Water (H2O) is generally sufficient although aqueous acid (H3O+) is more effective.
  • X here can be Cl, Br or I, depending on how the Grignard reagent is made.

Examples:

Mechanism:

The Grignard reagent adds to the carbon of the nitrile, forming a new carbon-carbon bond (Step 1, arrows A and B). This is stable until water and acid is added (Step 2, arrows C an D) which forms the imine. Protonation of the imine nitrogen (Step 3, arrows E and F) results in the formation of the iminium ion, which undergoes 1,2-addition by water (Step 4, arrows G and H). This species then undergoes proton transfer (Step 5, arrows I and J) to allow for the loss of ammonia (NH3) in a subsequent 1,2-elimination (Step 6, arrows K and L). Deprotonation of the carbonyl oxygen with base (Step 7, arrows M and N) then results in the ketone.

Notes:

  • Step 2 occurs only after the addition of aqueous acid. Note that a full equivalent of acid is necessary here to protonate the imine.
  • Other acids can be used: the use of Cl(-) as a counter-ion for H3O(+) here is arbitrary here and of no consequence in the reaction except to balance the charge from H3O(+).
  • Steps 3-7 are identical to those for the hydrolysis of imines.
  • Other reasonable mechanisms can be drawn for proton transfer.
  • Other bases could reasonably be used instead of water.
  • A protonated imine is called an “iminium”.

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{ 11 comments… read them below or add one }

Rajarshi Banerjee

If I do not add acid will the reaction stop at imines

Reply

Emm

It can especially if the R is aromatic.

Reply

Jared Hensley

why can you not attack a second time with another equiv of grignard? thanks!

Reply

James

The problem is that you’d essentially have a nitrogen with two negative charges on it – very unstable. So it tends to simply do mono-addition.

Reply

Alanckrit

no i think JARED is asking about why not the ketone formed further react with grignard reagent to give 3 degree alcohol….if it does is it a negative aspect of this reaction?? (if we wanted to get ketone)

Reply

James

The ketone isn’t formed until adding water, which would destroy any Grignard that is present.

Reply

Gauri

In case of HCN will the same reaction happen or will the H be removed and we will get CH4 and NCMgBr?

Reply

Gauri

Will the same reactin happen with HCN or will we get CH4 and CH3MgBr like an alkane reaction?

Reply

Manjoorahmed

Is that possible that alkyl cynide react with two moles of grignard reagent to give alkyl amine?

Reply

Alyssa

I thought N don’t usually leave?

Reply

James

If it’s protonated, it will.

Reply

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