Mechanism of Acyl Substitution

Acyl Subsitution

The first step in acyl substitution is an addition step, forming a tetrahedral intermediate.  This is exactly like the first step in the addition of nucleophiles to aldehydes and ketones.  In the second step, the tetrahedral intermediate loses the LG and the carbonyl is reformed.  The net effect is a substitution.

In this case, the Nu is negative ( -OH, -OR, -R, or H-) so the nucleophilic atom will become neutral.

Take NoteCheater Mechanism - Sometimes folks will shorten or abbreviate this mechanism as follows.



We will call this the "Cheater Mechanism".  When writing out and thinking about reactions it's often convenient to use this cheater mechanism, but please keep in mind the reaction really goes through a tetrahedral intermediate in which the carbonyl carbon changes from sp2 to sp3 hybrid.

 

The exact mechanism followed and the nature of the tetrahedral intermediates depends upon a number of factors including 1) nature of the carboxylic acid derivative, 2) the nature of the nucleophile and 3) whether under acid/basic nucleophilic conditions.

If the nucleophile is protonated and neutral (HOH, HOR, NHR2) then it will become positively charged in the tetrahedral intermediate.  In such cases, a deprotonation occurs.

For poor nucleophiles such as H2O or HOR and less reactive esters and amides, acidic or basic catalysis is often required.

For example, water will not readily undergo addition to esters, under neutral conditions.  The addition is energetically unfavorable.

 

Protonation of the carbonyl prior to nucleophilic attack "activates" the carbonyl for nucleophilic addition.  A protonated carbonyl is a better electrophile.  Can you draw the other resonance structure of the following protonated ester?

Take NoteUnder acidic conditions you should avoid forming negative charges on intermediates.

Under basic or nucleophilic conditions such as with NaOH or NaOR, the -OH or -OR, is a sufficiently strong nucleophile to attack directly.

Take NoteUnder basic/nucleophilic conditions you should avoid forming positively charged intermediates.  You can not protonate the carbonyl prior to nucleophilic attack.  Under these conditions, there are no protons around to protonate the carbonyl.