Substituent effects on the basicity (pKa) of aryl Q1 guanidines and 2-(arylimino)imidazolidines: correlations of pH-metric and UV-metric values with predictions from gas-phase ab initio bond lengths

The dissociation constants of two related series of 2-(arylimino)imidazolidine and aryl guanidine α-adrenoceptor antagonists (35 compounds in total) were measured by potentiometric titrations and by UV-spectrophotometry using the 96-well microtitre plate method. The experimental values obtained using both methods were quite consistent and showed a very good agreement with the pK values calculated using the AIBLHiCoS methodology, which uses only a single bond length obtained using ab initio calculations at a low level of theory. The prediction power of the imidazolidine and guanidine set of compounds was very good with deviations typically <0.30 and <0.24 pK units, and a mean absolute error (MAE) of 0.23 and 0.29, respectively. The study of the quantitative effect of diverse substituents on the basicity of aryl guanidine and 2-(arylimino)imidazolidine derivatives is useful for medicinal chemists working with biologically relevant guanidine-containing molecules.This work was supported by the Spanish Ministerio de Economia y Competitividad (Grant SAF2015-66690-R). B. A. Caine thanks BBSRC and Syngenta Ltd for PhD funding. P. L. A. P. acknowledges the EPSRC for funding through the award of an Established Career Fellowship (grant EP/K005472). We acknowledge the assistance of G. Romero and F. Peréz Gordillo (Instrumental Analysis Department at IQM) with the potentiometric pKa measurements. We thank Chanse`le Jourdan for her assistance with the UV-metric pKa measurements. Dr Rozas is gratefully acknowledged for the gift of the pyridino derivatives 16–22 and the Boc-protected precursors of compounds 1–10 and 23–27.Peer Reviewe