How Hydrogen Bonding Amplifies Isomeric Differences in Pyridones toward Strong Changes in Acidity and Tautomerism

Steric hindrance
of hydration and hydrogen bond enhancement by
localized charges have been identified as key factors for the massive
chemical differences between the hydroxypyridine/pyridone isomers
in aqueous solution. While all isomers occur mainly in the hydroxypyridine
form in the gas phase, they differ by more than 3 orders of magnitude
both in their acidity and tautomeric equilibrium constants upon hydration.
By monitoring the electronic and solvation structures as a function
of the protonation state and the O– substitution
position on the pyridine ring, the amplification of the isomeric differences
in aqueous solution has been investigated. Near-edge X-ray absorption
fine structure (NEXAFS) measurements at the N K-edge served as the
probe of the chemical state. The combination of molecular dynamics
simulations, complete active space self-consistent field (CASSCF),
and time-dependent density functional theory (TD-DFT) spectral calculations
contributes to unraveling the principles of tautomerism and acidity
in multiple biochemical systems based on tautomerism.