The Effects of Aromaticity Gain in Multipoint Hydrogen-Bonded Arrays

The aromaticity-modulated hydrogen bonding (AMHB) model was applied to understand how “aromaticity gain” influences the association strengths of multipoint hydrogen-bonded arrays and as a driving force for electronic complementarity in base pairing. The block-localized wavefuntion (BLW) method was used to quantify the degree of “aromaticity gain” (i.e., the amount of increased cyclic π-electron delocalization) in arrays upon hydrogen bonding. An excellent linear relationship was found between the computed gas-phase association free energies and the amount of increased cyclic π-electron delocalization energies of 26 triply (r = 0.940) and 20 quadruply (r = 0.959). Computational analyses for 57 hydrogen-bonded base pairs also document excellent linear correlation between the gas-phase association energies and the degree of aromaticity gain of paired bases (r = 0.949). Hydrogen bonding interactions can polarize the ring π-electrons to increase (or decrease) cyclic 4n + 2 π-electron delocalization, resulting in aromaticity gain (or loss) in complexes, and become strengthened (or weakened). Our findings point to important limitations of the secondary electrostatic interaction (SEI) model, suggesting the importance of considering aromaticity gain in arrays as a relevant factor for determining the stability of multipoint hydrogen-bonded complexes. This work shows that aromaticity gain increases the inherent association strengths of hydrogen-bonded complexes. Potential implications of the AMHB model for improving nucleic acid force-fields and for designing robust unnatural base pairs are also discussed.