Weak nucleophiles are not strong enough to add to a simple C=O bond.  They require the carbon to be made more electrophilic, and this can be done using either a Lewis acid or simply H⁺. We will focus on activation using simple acid – a process called protonation.  This leads to an activated, charged form of the C=O which is now electrophilic enough to react with even weak nucleophiles via nucleophilic addition.

Most often the weak nucleophiles are uncharged compounds such as alcohols (ROH) or amines (RNH₂ or similar).  With these neutral 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.

Mechanism

1)  Protonation of the carbonyl

2)  Nucleophilic addition to the activated carbonyl

3) Deprotonation

Contributors

• Prof. Steven Farmer (Sonoma State University)