Exercise 8 | Amino Acids, Peptides and Proteins

Organic Chemistry 3 - Exercise 8

The amino acid histidine has two potentially basic N sites (N1 and N2), which one is more basic and why?

Basicity: study the stability of the protonated product.

Both of the N atoms are part of an aromatic system, which is particularly stable.
For N1, the lone pair is not part of the aromatic system ⇒ the protonated form is still aromatic.
For N2, the lone pair is involved in the aromatic sextet ⇒ the protonated form is a non-aromatic system and so less stable.

Hence N2 is not very basic and protonation at N1 will be favoured.