Overview

• Nitriles typically undergo nucleophilic addition to give products that often undergo a further reaction.
• The chemistry of the nitrile functional group, CºN, is very similar to that of the carbonyl, C=O of aldehydes and ketones. Compare the two schemes:

        versus 

• However, it is convenient to describe nitriles as carboxylic acid derivatives because:
• the oxidation state of the C is the same as that of the carboxylic acid derivatives.
• hydrolysis produces the carboxylic acid
• Like the carbonyl containing compounds, nitriles react with nucleophiles via two scenarios:

• Strong nucleophiles (anionic) add directly to the CºN to form an intermediate imine salt that protonates (and often reacts further) on work-up with dilute acid.

            Examples of such nucleophilic systems are :  RMgX, RLi, RCºCM, LiAlH₄
 
• Weaker nucleophiles (neutral) require that the CºN be activated prior to attack of the Nu.

     This can be done using a acid catalyst which protonates on the Lewis basic N and makes the system more electrophilic.

 




            Examples of such nucleophilic systems are :  H₂O, ROH
 

The protonation of a nitrile gives a structure that can be redrawn in another resonance form that reveals the electrophilic character of  the C since it is a carbocation.

Hydrolysis of Nitriles

Summary

• Nitriles, RCºN, can be hydrolyzed to carboxylic acids, RCO₂H via the amide, RCONH₂.
• Reagents : Strong acid (e.g. H₂SO₄) or strong base (e.g. NaOH) / heat.

• Hydrolysis of Esters and Amides

MECHANISM OF THE ACID catalyzed HYDROLYSIS OF NITRILES
Step 1: An acid/base reaction. Since we only have a weak nucleophile so activate the nitrile, protonation makes it more electrophilic.
Step 2: The water O functions as the nucleophile attacking the electrophilic C in the CºN, with the electrons moving towards the positive center.
Step 3: An acid/base reaction. Deprotonate the oxygen that came from the water molecule. The remaining task is a tautomerization at N and O centers.
Step 4: An acid/base reaction. Protonate the N gives us the -NH2 we need....
Step 5: Use the electrons of an adjacent O to neutralise the positive at the N and form the p bond in the C=O.
Step 6: An acid/base reaction. Deprotonation of the oxonium ion reveals the carbonyl in the amide intermediate....halfway to the acid.....  What about the rest ?

Reduction of Nitriles
(for more detail see Chapter 22)

Reactions usually in Et₂O or THF followed by H₃O⁺ work-up

Summary

• The nitrile, RCºN, gives the 1^o amine by conversion of the CºN to -CH₂-NH₂
• Nitriles can be reduced by LiAlH₄ but NOT the less reactive  NaBH₄
• Typical reagents :  LiAlH₄  / ether solvent followed by aqueous work-up.
• Catalytic hydrogenation (H₂ / catalyst) can also be used giving the same products.
• R may be either alkyl or aryl substituents

Reactions of RLi or RMgX with Nitriles

Reaction usually in Et₂O or  THF

Summary:

• Nitriles, RCºN, react with Grignard reagents or organolithium reagents to give ketones.
• The strongly nucleophilic organometallic reagents add to the CºN bond in a similar fashion to that seen for aldehydes and ketones.
• The reaction proceeds via an imine salt intermediate that is then hydrolyzed to give the ketone product.

• Since the ketone is not formed until after the addition of water, 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.

REACTION OF RMgX WITH AN NITRILE
Step 1: The nucleophilic C in the organometallic reagent adds to the electrophilic C in the polar nitrile group. Electrons from the CºN 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 electrophilic C with the p bond breaking to neutralize the change on the N.
Step 5: An acid/base reaction. Deprotonate the O from the water molecule to neutralize 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 of the ketone product.

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