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Chapter 20: Carboxylic Acid Derivatives. Nucleophilic Acyl Substitution



Summary | Carboxylic Acids Derivatives | Nucleophilic Acyl Substitution | Reactions of Carboxylic Acid Derivatives | Spectroscopic Analysis | Self Assessment | Quiz |


Nucleophilic Acyl Substitution

Chapter 20: Carboxylic Acid Derivatives. Nucleophilic Acyl Substitution


Overview of Nucleophilic Acyl Substitution


Overall nucleophilic acyl substitution is most simply represented as follows:
nucleophilic acyl substitution
What does the term "nucleophilic acyl substitution" imply ?

A nucleophile is an electron rich species that will react with an electron poor species (Nu in scheme).
An acyl group is R-C=O (where R can be alkyl or aryl).... note the acyl group in both the starting material and the product.

A substitution note that the leaving group (LG) is replaced by the nucleophile (Nu).

There are two fundamental events in a nucleophilic acyl substitution reaction:

Overall, these events are the same as those in a simple nucleophilic substitution (chapter 8), note the fundamental similarity in the two general processes. nucleophilic substitution

The difference in nucleophilic acyl substitution is that when the nucleophile adds to the electrophilic C, it becomes tetrahedral and an intermediate forms, then the leaving group departs as shown below:

nucelophilic acyl substitution

Question:
In nucleophilic substitution (e.g. for alkyl halides) the nucleophile cannot attack until the leaving group leaves, why is there a difference ? the sp3 C of an alkyl halide would have to become pentavalent


 

Nucleophilic Acyl Substitution : Reactive Systems

If either of the reaction components are very reactive, for example the nucleophile (e.g. anionic nucleophiles such as HO- etc.) or the electrophile, the carboxylic acid derivative (e.g. acyl chlorides or acid anhydrides) then the reaction can occur directly as shown below.
This is similar to what we have talked about previously for the reactions for epoxides (Chapter 16) and aldehydes / ketones (Chapter 17) with stronger nucleophiles.
 
 

NUCLEOPHILIC ACYL SUBSTITUTION FOR REACTIVE SYSTEMS
Step 1:
The nucleophile adds to the electrophilic C in the polar carbonyl group, electrons from the C=O move to the electronegative O creating the tetrahedral intermediate.
nucleophilic acyl substitution for reactive systems
Step 2:
The intermediate collapses, reforming the strong C=O bond results in the loss of the leaving group, leading to the new carbonyl containing system.

 

Nucleophilic Acyl Substitution : Less Reactive Systems

If the reaction components are less reactive, for example the nucleophile (e.g.  neutral nucleophiles such as H2O or ROH etc.) or the electrophile, the carboxylic acid derivative (e.g. esters or amides) then the reaction will be very slow unless the reaction is promoted.

This is similar to what we have talked about previously for the reactions epoxides (Chapter 16) and aldehydes / ketones (Chapter 17) with weaker nucleophiles.
 
 
NUCLEOPHILIC ACYL SUBSTITUTION FOR LESS REACTIVE SYSTEMS
Step 1:
An acid / base reaction. Protonation of a lone pair on the O of the carbonyl group, this creates a more electrophilic, cationic system. 
 

Step 2:
The nucleophile attacks the electrophilic C of the carbonyl group causing the p bond in the C=O to break and allows for neutralization of the positive charge. This converts the sp2 C=O into the sp3 tetrahedral intermediate. 
 
 

Step 3:
Electrons on the O are used to aid the loss of the leaving group (see note below). This reforms the p bond of the carbonyl group. 
 
 
 

Step 4:
An acid/base reaction. Deprotonation reveals the carbonyl of the product and regenerates the acid catalyst.

acid catalysed nucleophilic acyl substitution for less reactive systems

Note:  In some cases (especially esters and amides) the leaving group must also be activated prior to being lost. This can also be achieved by protonation. This adds a step to the process shown above.

Examples Reactions that follow this mechanism:



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