Chapter 20: Carboxylic Acid Derivatives. Nucleophilic Acyl Substitution

Reactions of RLi or RMgX with Nitriles

Reaction usually in Et₂O or  THF

Reaction type:  Nucleophilic Acyl Substitution then Nucleophilic Addition

Summary:

• Nitriles, RC≡N, react with Grignard reagents or organolithium reagents to give ketones.
• The strongly nucleophilic organometallic reagents add to the C≡Nbond in a similar fashion to that seen for aldehydes and ketones.
• The reaction proceeds via an imine salt intermediate that is then hydrolysed to give the ketone product.

• Since the ketone is not formed until after the addition ofwater, the organometallic reagent does not get the opportunity to react with the ketone product.
• Nitriles are less reactive than aldehydes and ketones.
• The mechanism is an example of the reactive system type.

MECHANISM FOR THE REACTION OF RMgX WITH A NITRILE
Step 1: The nucleophilic C in the organometallic reagent adds to theelectrophilic C in the polar nitrile group. Electrons from the C≡N move to the electronegative N creating an intermediate imine salt complex.
Step 2: An acid/base reaction. On addition of aqueous acid, the intermediate salt protonates giving the imine.
Step 3: An acid/base reaction. Imines undergo nucleophilic addition, but require activation by protonation (i.e. acid catalysis).
Step 4: Now the nucleophilic O of a water molecule attacks the electrophilicCwith the π bond breaking to neutralise the change on the N.
Step 5: An acid/base reaction. Deprotonate the O from the water molecule to neutralise the positive charge.
Step 6: An acid/base reaction. Before the N system leaves, it needs to be made into a better leaving group by protonation.
Step 7: Use the electrons on the O in order to push out the N leaving group, a neutral molecule of ammonia.
Step 8: An acid/base reaction. Deprotonation reveals the carbonyl group ofthe ketone product.

© Dr. Ian Hunt, Department of Chemistry