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Obviously, there are general stability arguments that can be made to estimate relative pKas, such as evaluating the stability of the conjugate base of an acid, or thinking about how polarized the bond to hydrogen is.

However, is there a theory that can be absolute and account for the many exceptions to the above guidelines? What are the factors that are preventing a rigorous theory from being proposed?

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    $\begingroup$ Unfortunately acid/base strengths are still major weak points in quantum theory; there are no rigorous and affordable theories or approximations available. Most approaches have to be calibrated against highly accurate experimental measurements. $\endgroup$ – Martin - マーチン Jun 25 at 20:58
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    $\begingroup$ This 2015 review article is behind a paywall, but its abstract seems to provide a good summary of the state of the field, namely that it continues to be an active area of research, and there are two basic approaches researchers are pursing: onlinelibrary.wiley.com/doi/abs/10.1002/wcms.1218 $\endgroup$ – theorist Jun 26 at 1:38
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    $\begingroup$ @theorist the article you mention is available to the public, either on request on research gate (researchgate.net/publication/…) or directly and freely (no paywall), e.g., mercuryconsortium.org/furman/pubs/SeyboldsS2015.pdf $\endgroup$ – Buttonwood Jun 26 at 20:55
  • $\begingroup$ thanks for the responses, I talked to Seybold, and it seems that using rigorous quantum chemical calculations is too computationally expensive. It is the solvent effects and the corresponding entropy changes that make things complicated really fast. $\endgroup$ – Nathan Matthieu Tang Jul 9 at 0:11
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    $\begingroup$ @NathanMatthieuTang It would be great if you could summarize the comments and your conversation with Seybold in an answer to your own question. $\endgroup$ – Karsten Theis Nov 27 at 19:46

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