The fundamental nature and importance of electrostatic potential in hydrogen bond formation: a case study of heterocycles frequently observed in drugs

Abstract

Molecular electrostatic potential (MESP) analysis is employed to predict the hydrogen bond (HB) interaction strength (Eint) of frequently encountered chemical motifs (CO–HC, CN–HN, CN–HC, CF–HC, and CN–OC) in commonly observed heterocyclic rings in drugs with H2O using the M06L/6-311++G(d,p) level of DFT. The Eint of ring⋯H2O complexes is rationalized in terms of the MESP change observed at the nuclei of heteroatoms, viz. ΔVn(CN), ΔVn(CF) and ΔVn(CO) as well as that at the hydrogen atom, viz. ΔVn(NH) and ΔVn(CH). The ordered pair of (ΔVn of heteroatom, ΔVn of H atom) in the ring molecule showed the (+, +), (+, −), (−, +), and (−, −) variations with respect to a reference molecule. The (−, +) MESP behaviour always strengthened the (ring)heteroatom⋯Hw and Ow⋯H(ring) interactions while the (+, −) behaviour weakened these interactions. Furthermore, the (+, −) and (−, +) behaviours led to mixed Eint responses. Linear regression models based on two ΔVn parameters have been derived, producing solid predictions on even the finest changes in the Eint values of the five categories of ring molecules. The MESP hypotheses led to a profound understanding of the contributions of individual HBs within the realm of bidentate interactions. The ΔVn parameters have emerged as very sensitive electronic properties to understand even the subtle variations in the HB strength of molecular interactions, which offer a priori prediction of HB strength as well as suggest the tunability of HB strength within drug motifs.