Scaffold Effects on Halogen Bonding Strength

Halogen bonds have become increasingly
popular interactions in
molecular design and drug discovery. One of the key features is the
strong dependence of the size and magnitude of the halogen’s
σ-hole on the chemical environment of the ligand. The term σ-hole
refers to a region of lower electronic density opposite to a covalent
bond, e.g., the C-X bond. It is typically (but not always) associated
with a positive electrostatic potential in close proximity to the
extension of the covalent bond. Herein, we use a variety of 30 nitrogen-bearing
heterocycles, halogenated systematically by chlorine, bromine, or
iodine, yielding 468 different ligands that are used to exemplify
scaffold effects on halogen bonding strength. As a template interaction
partner, we have chosen N-methylacetamide representing
the ubiquitously present protein backbone. Adduct formation energies
were obtained at a MP2/TZVPP level of theory. We used the local maximum
of the electrostatic potential on the molecular surface in close proximity
to the σ-hole, VS,max, as a descriptor
for the magnitude of the positive electrostatic potential characterizing
the tuning of the σ-hole. Free optimization of the complexes
gave reasonable correlations with VS,max but was found to be of limited use because considerable numbers
of chlorinated and brominated ligands lost their halogen bond or showed
significant secondary interactions. Thus, starting from a close to
optimal geometry of the halogen bond, we used distance scans to obtain
the best adduct formation energy for each complex. This approach provided
superior results for all complexes exhibiting correlations with R2 > 0.96 for each individual halogen. We evaluated the dependence
of VS,max from the molecular surface onto
which the positive electrostatic potential is projected, altering
the isodensity values from 0.001 au to 0.050 au. Interestingly, the
best overall fit using a third-order polynomial function (R2 = 0.99, RMSE = 0.562 kJ/mol) with rather smooth transitions between
all halogens was obtained for VS,max calculated
from an isodensity surface at 0.014 au.