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

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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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