Linear free-energy relationships between a single gas-phase ab initio equilibrium bond length and experimental pKa values in aqueous solution.
Remarkably simple yet effective linear free energy relationships were discovered between a single ab initio computed bond length in the gas phase and experimental pKa values in aqueous solution. The formation of these relationships is driven by chemical features such as functional groups, meta/para substitution and tautomerism. The high structural content of the ab initio bond length makes a given data set essentially divide itself into high correlation subsets (HCSs). Surprisingly, all molecules in a given high correlation subset share the same conformation in the gas phase. Here we show that accurate pKa values can be predicted from such HCSs. This is achieved within an accuracy of 0.2 pKa units for 5 drug molecules.
Instituto de Química Médica (IQM-CSIC), Juan de la Cierva, 3, 28006 Madrid (Spain). ibon@iqm.csic.es.
Ibon
I
Alkorta
Paul L A
PL
Popelier
D000085:Acetates / Q000737:chemistry; D005740:Gases / Q000737:chemistry*; D006877:Hydroxamic Acids / Q000737:chemistry; D007700:Kinetics; D008956:Models, Chemical; D010648:Phenylacetates / Q000737:chemistry; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
D000085:Acetates; D005740:Gases; D006877:Hydroxamic Acids; D010648:Phenylacetates; D014867:Water; C025136:phenylacetic acid; C006696:benzohydroxamic acid; C415326:phenoxyacetic acid
ab initio; bond length; drugs; linear free energy relationship; pKa prediction