10.1021/jp107890p.s001
Junming Ho
Junming
Ho
Michelle L. Coote
Michelle L.
Coote
Marco Franco-Pérez
Marco
Franco-Pérez
Rodolfo Gómez-Balderas
Rodolfo
Gómez-Balderas
First-Principles Prediction of the p<i>K</i><sub>a</sub>s of Anti-inflammatory Oxicams
American Chemical Society
2010
macroscopic pKa values
benchmarking study
latter approach
error cancellation
solution conformers
oxicam derivatives
MAD
diprotic acids
pKa prediction
proton exchange scheme
SMD
theory methods
pKa calculation
proton exchange cycle
protonation state
cycle calculations
method G 3MP Oxicams
model
2010-11-11 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/First_Principles_Prediction_of_the_p_i_K_i_sub_a_sub_s_of_Anti_inflammatory_Oxicams/2713996
The gas- and aqueous-phase acidities of a series of oxicams have been computed by combining M05-2X/6-311+G(3df,2p) gas-phase free energies with solvation free energies from the CPCM-UAKS, COSMO-RS, and SMD solvent models. To facilitate accurate gas-phase calculations, a benchmarking study was further carried out to assess the performance of various density functional theory methods against the high-level composite method G3MP2(+). Oxicams are typically diprotic acids, and several tautomers are possible in each protonation state. The direct thermodynamic cycle and the proton exchange scheme have been employed to compute the <i>microscopic</i> p<i>K</i><sub>a</sub>s on both solution- and gas-phase equilibrium conformers, and these were combined to yield the <i>macroscopic</i> p<i>K</i><sub>a</sub> values. Using the direct cycle of p<i>K</i><sub>a</sub> calculation, the CPCM-UAKS model delivered reasonably accurate results with MAD ∼ 1, whereas the SMD and COSMO-RS models’ performance was less satisfactory with MAD ∼ 3. Comparison with experiment also indicates that direct cycle calculations based on solution conformers generally deliver better accuracy. The proton exchange cycle affords further improvement for all solvent models through systematic error cancellation and therefore provides better reliability for the p<i>K</i><sub>a</sub> prediction of compounds of these types. The latter approach has been applied to predict the p<i>K</i><sub>a</sub>s of several recently synthesized oxicam derivatives.