Question

HEPES is 2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethane-1-sulfonic acid. I have read (MA Al-Ghobashy, Bull of Faculty of Pharmacy, Cairo University 2014; 52: 71-78) that the sulfonic acid group is completely dissociated over almost the whole pH range and there are two basic nitrogens N1 and N2 stated to have pKa 3 and 7.5 in the mentioned paper and in Wikipedia article. But what is the pKa of the sulfonic acid group? And, in the opposite end we have an OH group - is this inert or does it ever give off the proton?

Answer 1

The sulfonic acid group in HEPES does not have a practical pKa value as it is completely dissociated over almost the entire pH range, similar to the first proton of sulfuric acid. The hydroxyl group in HEPES is very weakly acidic, with a pKa around 16, and thus generally does not give off its proton.

Step-by-step explanation:

The dissociation of the sulfonic acid group in HEPES is typically complete over a wide pH range because sulfonic acids like HEPES are generally strong acids.

The exact pKa of the sulfonic acid group in HEPES is not commonly referenced due to its complete dissociation, which is analogous to the behavior of sulfuric acid's first proton.

For sulfuric acid, the first proton is completely dissociated, which doesn't allow for a practical pKa to be defined since it's a strong acid.

On the opposite side, the hydroxyl (-OH) group in HEPES is relatively inert in terms of acidity when compared to the sulfonic acid group.

The pKa for aliphatic alcohols is approximately 16, similar to water, indicating that this group is very weakly acidic. Consequently, the hydroxyl group in HEPES is not expected to donate its proton readily under physiological conditions.