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Everywhere on the internet I see that the two $\mathrm pK_\mathrm a$'s of ketoconazole are 6.4 and 2.3, but I don't think that is correct.

The $\mathrm pK_\mathrm a$ of imidazole is around 6.4 . But ketoconazole also has a piperazine ring and normally this $\mathrm pK_\mathrm a$ is around 9.8. There are electron acceptors but I still find 2.3 to be very low. Is this correct and which of the two nitrogens will be protonated?

ketoconazole

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  • $\begingroup$ Can you provide references for the values you're seeing everywhere on the internet? Here is a 2-year old presentation from UCB Celltech in which the p$K_{\rm a}$ values for ketoconazole are given as 6.43 and 3.64. $\endgroup$ – Todd Minehardt Aug 18 '15 at 20:19
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The 6.4 pKa is close to the reported pKa of imidazole (6.95), so 6.4 is at the imidazole ring.

That leaves pKa 2.3 (or 3.64) for the other basic nitrogen. While that nitrogen is part of a piperazine, piperazine itself (pKa 9.8) isn't a good comparison. The nitrogen in question is also conjugated to an aromatic ring, so it would be better to look at aniline, with a pKa of 4.6. That's much closer to ketoconazole. Add in the inductive effect of the proximal amide, and a pKa in the 2-3 range makes sense.

enter image description here

Many common pKa's can be found on Prof. Dave Evans's pKa list.

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