A database of steric and electronic properties of heteroaryl substituents

Abstract

Abstract Heteroaryl substituents are important building blocks of functionalized organic compounds in drug discovery, materials science, and catalysis. Quantitative descriptions of steric and electronic properties of heteroaryl substituents are essential in establishing structure-activity relationships and predicting reactivity and properties of heteroaromatic compounds. We introduce HArD, the HeteroAryl Descriptors database, comprising DFT-computed steric and electronic descriptors of >31,500 heteroaryl substituents. The database features heteroaryl substituents comprising 5- and 6-membered rings as well as 5,6- and 6,6-fused ring systems. Different regioisomers and additional substituents on the heteroaromatic ring were included to describe the diverse chemical space of heteroaryl substituents. The database includes 65 descriptors such as buried volume and Sterimol parameters to describe steric effects, atomic charges and HOMO/LUMO coefficients and energies to describe electronic effects, and Harmonic Oscillator Model of Aromaticity (HOMA) values describing aromaticity. In addition, we developed Hammett-type heteroaryl substituent constants (σ Het) based on computed heteroaryl carboxylic acid pK a values, which aim to extend the broadly used Hammett constants (σ p and σ m) from substituted phenyl groups to substituted heteroaryl groups.