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Biology LibreTexts

A8. Reactions of Histidine

Histidine is one of the strongest bases at physiological pH's. The nitrogen atom in a secondary amine might be expected to be a stronger nucleophile than a primary amine through electron release to that N in a secondary amine.  Opposing this effect is the steric hindrance by the two attached Cs of the N on attach on an electrophile .  However, in His, this steric effect is minimized since the 2Cs are restrained by the ring. With a pKa of about 6.5, this amino acid is one of the strongest available bases at physiological pH (7.0). Hence, it can often cross-react with many of the reagents used to modify Lys side chains. His reacts with reasonably high selectivity with diethyl pyrocarbonate.



Figure:  Where is the H on His?  Where is the Charge?