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 (E_int) 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 E_int of ring⋯H₂O complexes is rationalized in terms of the MESP change observed at the nuclei of heteroatoms, viz. ΔV_n(CN), ΔV_n(CF) and ΔV_n(CO) as well as that at the hydrogen atom, viz. ΔV_n(NH) and ΔV_n(CH). The ordered pair of (ΔV_n of heteroatom, ΔV_n 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⋯H_w and O_w⋯H(ring) interactions while the (+, −) behaviour weakened these interactions. Furthermore, the (+, −) and (−, +) behaviours led to mixed E_int responses. Linear regression models based on two ΔV_n parameters have been derived, producing solid predictions on even the finest changes in the E_int 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 ΔV_n 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.