Linear Free‐Energy Relationships between a Single Gas‐Phase Ab Initio Equilibrium Bond Length and Experimental p K a 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 p K a 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 p K a values can be predicted from such HCSs. This is achieved within an accuracy of 0.2 p K a units for 5 drug molecules.