Can semi-empirical calculations yield reasonable estimates of hydrogen-bonding basicity? The case of nitriles

Abstract

Descriptors of hydrogen-bond basicity (enthalpy of hydrogen-bond formation, hydrogen-bond length and minimum electrostatic potential of the base) have been calculated by the AM1 and PM3 methods for hydrogen-bond formation between 4-fluorophenol and numerous nitriles embracing a large range of structures and basicity. The AM1 method heavily underestimates the enthalpy of hydrogen-bond formation and the hydrogen-bond length compared to PM3, but, from a relative point of view, correlations between the hydrogen-bond basicity scale pK_HB and quantum-mechanical descriptors calculated with AM1 have a better predictive power. These correlations allow the extension of the pK_HB scale and the treatment of polyfunctional nitriles. The subtle effects of alkyl groups in alkyl cyanides, cyanamides and cyanoguanidines are correctly predicted. The antiulcer drug cimetidine is found to possess a super-basic nitrile group which could be hydrogen-bonded to an hydrogen-bond donor site of the H₂ receptor.