HYDROLYSIS OF NITRILES     Reaction type:  Nucleophilic Addition

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

Reaction type:  Nucleophilic Addition then Nucleophilic Acyl Substitution

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.

Related Reactions

• 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.....

 

Reactions usually in Et₂O or THF followed by H₃O⁺ work-up Reaction type: Nucleophilic Addition

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 Reaction type:  Nucleophilic Acyl Substitution then Nucleophilic Addition

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. PROBLEM The chemistry of the nitrile functional group, CºN, is very similar to that of the carbonyl, C=O of aldehydes and ketones. but why nitrile is less reactive than aldehydes or ketones?         versus   as nitrile containing a triple bond to be decided by a nucleophile while aldehyde or ketone containing only double bonds. obviously a little difficult for nucleophiles react with nitri compared with aldehyde or ketone. so that the nitrile is less reactive than the aldehyde or ketone group, although both have similar chemical properties.