21.2 General mechanism

 

General mechanism for addition of weak nucleophiles to carbonyls

Recall (from chapter 20) that strong nucleophiles are able to add directly to a C=O based on the type I resonance of the C=O bond that makes the carbon moderately electrophilic.  However, weak nucleophiles are not strong enough to add to C=O in this way.  They require the carbon of the C=O to be made more electrophilic, and this is done using either a Lewis acid or simply H+ (which in practice usually means a strong acid such as H2SO4).  We will focus on activation using simple acid – a process called protonation.  This activated, charged form of the C=O now is a stronger electrophile, with a bigger positive charge (via type III resonance) on the carbon so even weak nucleophiles will attack, allowing nucleophilic addition to occur.
Overview comparing nucleophilic addition without activation (chap 20) with the acid-catalyzed nucleophilic addition discussed in chapter 21 (this chapter).
Most often the weak nucleophiles are uncharged compounds such as alcohols (ROH) or amines (RNH2 or similar).  With these uncharged nucleophiles, the product of the nucleophilic addition step is a positively charged compound, and so there is usually a final acid-base step to remove the unwanted H+ (“deprotonation”) and form the final uncharged product.

Detailed mechanism

STEP 1: Protonation on oxygen (an acid-base step) activates the carbonyl.

STEP 2: The weak nucleophile attacks this activated C=O via nucleophilic addition.

STEP 3: Finally, deprotonation (loss of H+) occurs by another acid-base step.  We have used a second molecule of HNuc: as the base here, but you may also use the A- (produced in the first step) as your base for this step.

Note that the overall starting molecule and product here are equivalent to what we saw in chapter 20 with strong nucleophiles, i.e., the outcome of the nucleophilic addition is the same.  However, the mechanism (the route from reactant to product) is different.

Graphic showing protonation on oxygen (acid-base), attack of the nucleophile (nucleophilic addition) then loss of H+ (acid-base). Overall, this gives addition of a nucleophile to a C=O.

Summary

In conclusion, there are two ways to add nucleophiles to C=O.

(a) Strong nucleophiles (Nuc-, covered in chapter 20) do simple addition to C=O

Nucleophile adds to C=O, then O-minus is protonated

 

 

 

(b) Weak nucleophiles (HNuc:) only add to activated C=O (covered in THIS chapter, chapter 21).

Acid protonates the oxygen of C=O, then nucleophile adds, then H+ is lost to give the nucleophilic addition product.

 

 

 

In the rest of this chapter, we will explore in detail how this latter mechanism works in practice for different weak nucleophiles.

Contributors

  • Prof. Martin A. Walker (SUNY Potsdam)