Field of Science

pKa bamboozle

In a recent publication by a famous chemist, I came across this illustration in which they have calculated the pKa values of guanine and xanthine, among other bases.

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Not only does the NH in the five membered ring in xanthine have a lower pKa than the NH next to the carbonyl in the six membered ring, but the pKa of the NH next to the carbonyl in the six membered ring does not change at all when you go from guanine to xanthine.

Maybe I have just had a long day, but this does not make sense to me at all. For the love of god, explain.


  1. This is interesting. I have not read the paper, but I suspect that there is not a lot of experiemental verification of the predictions, right? (if it is a computer-model paper)

    One comment though about Xanthene. I can see the NH between the two carbonyls having a pKa that is similar to Guanine, here is why: In Xanthene, one might expect the additional carbonyl to greatly reduce the pKa, much like dimedone or Meldrums acid. The difference here is that the anion that is generated upon deprotonation is not in conjugation with carbonyls (that spot is taken up by the lone pair), so there is not net stabilization, hence, no great change in pKa.

    Now, I would expect some change, but this is a calculation paper, right?

    Could you post the DOI? (or mail me a copy)

  2. Maybe the +M effect of the amino group raises the pKa for the 9N in guanine because it transfers charge over there. Therefore the pKa would be so much lower in Xanthine.

  3. That could be part of the explanation, yes.

  4. Your blog post came up as I was searching for dimedone pKa. However, I don't understand your confusion. I can see that these are not measured pKa values as protonation of one atom will decrease the pKa of other atoms. I don't think that was taken into account, but I don't have the paper. The net effect is that the carbonyl group has decreased the electron availability on all of the heteroatoms. This is what I would have expected. It can seem odd to have pKa of conjugate acids and acids mixed together in a single structure, but I can figure that as well.

    Let's go through it though anyway, it is your question. Let's start with Guanine N1 (6 o'clock), 1.1 vs xanthine oxygen (5 o'clock), -10.6. Pretty high, but in the right direction.
    Guanine NH2 pKa (5 o'clock), missing, versus X N1H, (6 o'clock), 6.4.
    G, N3H, 9.6, X, N3H, 9.6.
    G, O, -5.4, X, O, -8.6, this is the effect of the carbonyl at C2.
    G, N7, 3.2, vs X N7, 0.5, this is the C2-C=O effect again on the conjugate acid.
    G, N9, 10, vs X, N9 7.3, this is a vinylogous amide with C4-C=O. The C2-C=O is exerting its effect again.

    The only effect I am surprised about it the small change of the N3-NH.

  5. wepplo, I believe he is confused about the lower pKa of the N3 as compared to the N7 on xanthine.
    The lone pair on the NH in the 6-membered ring (N3) between the carbonyls is part of an aromatic system (2e- from the NH in question, two from the double bond, and two from the other NH (N1) in the 6-membered ring). If you deprotonate it further, then you have a few options:
    you can destroy aromaticity on the 6-membered ring and create double bond character on both sides of the N, causing considerable ring strain
    you can simply leave the negative charge on the nitrogen (in an sp2 orbital, if you like hybridization as a model), spare aromaticity, and spare ring strain, but this leaves a naked point charge, which is decidedly unstable...
    Now clearly you do a bit of both, which is partly why the pKa is lower than would be expected for N- (35ish?), but higher than that for the NH on the five-membered ring which CAN easily delocalize because the five-membered ring is not likely the preferred aromatic system (smaller ring, not quite 120, bond overlap not good), and the 6-membered ring can maintain its aromaticity.
    now as for why this order is reversed on guanosine, I really have no clue!
    Hope this helps (despite being 3 years after you posted it...)
    Alexander Roy
    (S*and*er_R*oy@h*ot*mai**m) remove astrices to use...


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